CN107660207B - Buprenorphine acetate and method for preparing buprenorphine - Google Patents

Buprenorphine acetate and method for preparing buprenorphine Download PDF

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CN107660207B
CN107660207B CN201680027202.2A CN201680027202A CN107660207B CN 107660207 B CN107660207 B CN 107660207B CN 201680027202 A CN201680027202 A CN 201680027202A CN 107660207 B CN107660207 B CN 107660207B
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buprenorphine
less
free base
acetate
blend
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CN107660207A (en
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C·弗雷德里克·M·亨特利
埃里克·韦恩·卡泰斯托
黑尔格·阿尔弗雷德·赖施
阿尔沙纳·夏尔马
亚克·拉里·斯蒂米斯特
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Rhodes Technologies Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems
    • C07D489/10—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14
    • C07D489/12—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14 the bridge containing only two carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The present disclosure provides acetate salts of buprenorphine, and the anhydrates, solvates, hydrates, and crystalline forms thereof, wherein the acetate salt of buprenorphine is substantially free of impurities. The present disclosure also provides methods of making the acetate salts, buprenorphine free base prepared from the acetate salts, other salts prepared from the free base, and pharmaceutical compositions thereof substantially free of impurities.

Description

Buprenorphine acetate and method for preparing buprenorphine
Background
Buprenorphine is an opioid useful in the treatment of opioid addiction and in the management of pain, such as moderate pain. Traditional methods for synthesizing buprenorphine use thebaine or oripavine as starting materials. These known methods of buprenorphine synthesis typically result in impurity levels above levels acceptable according to the international harmonization ("ICH") guidelines for the requirements of human drug registration technology. Examples of impurities which may be present at unacceptable levels in buprenorphine formulations include (4R, 4aS, 6R, 7aR, 12bS) -3- (but-3-en-1-yl) -6- ((S) -2-hydroxy-3, 3-dimethylbut-2-yl) -7-methoxy-1, 2,3, 4,5, 6, 7,7 a-octahydro-4 a, 7-ethan-4, 12-methanobenzofuro [3, 2-e ] isoquinolin-9-ol and (4R, 4aS, 6R, 7aR, 12bS) -3- (cyclopropylmethyl) -6- ((S) -2-hydroxy-3, 3-dimethylbut-2-yl) -1, 2,3, 4,5, 6, 7,7 a-octahydro-4 a, 7-ethylbridged-4, 12-methanobenzofuro [3, 2-e ] isoquinoline-7, 9-diol. Some purification methods, such as chromatography, for example, as disclosed in U.S. patent No. 8,492,547 can provide buprenorphine with acceptable levels of impurities, but with associated higher costs or are difficult to apply on a commercial scale. Thus, there is a need for alternative routes for the preparation of buprenorphine that contain acceptable levels of impurities.
Summary of The Invention
One aspect of the present disclosure relates to acetate salts of buprenorphine.
Another aspect of the disclosure relates to buprenorphine acetate tetrahydrate.
Another aspect of the present disclosure relates to a crystalline form of the acetate salt of buprenorphine.
Another aspect of the present disclosure relates to a crystalline form of buprenorphine acetate tetrahydrate.
Another aspect of the present disclosure relates to a method for preparing an acetate salt of buprenorphine, the method comprising the steps of:
(a) contacting buprenorphine free base with a solution comprising acetic acid in a dissolution vessel to form a blend, wherein the blend is at a temperature of about 40 ℃ to about 80 ℃;
(b) optionally filtering the blend of step (a);
(c) adding a reagent to the admixture produced in step (a) or (b) to precipitate the acetate salt of buprenorphine; and
(d) isolating the acetate salt of buprenorphine precipitated in step (c).
Another aspect of the present disclosure relates to a method for preparing buprenorphine free base, comprising the steps of:
(a) contacting an acetate salt of buprenorphine with the solution and a basic material to form a blend;
(b) agitating the admixture of step (a) at a temperature of about 20 ℃ to about 90 ℃ to provide buprenorphine free base;
(c) isolating the buprenorphine free base of step (b); and
(d) optionally repeating steps (a) to (c) one or more times.
Another aspect of the present disclosure relates to a method for preparing buprenorphine free base, comprising treating an acetate salt of buprenorphine at a pressure, temperature, and for a period of time sufficient to remove acetic acid and water, thereby providing buprenorphine free base.
Another aspect of the present disclosure relates to a method for preparing buprenorphine free base, comprising the steps of:
(a) dissolving an acetate salt of buprenorphine in a solution to form a blend;
(b) optionally filtering the blend of step (a);
(c) adding a basic material to the blend of step (a) or (b) to form a second blend;
(d) adding an anti-solvent to the second admixture produced in step (c) to form a precipitate of buprenorphine free base; and
(e) isolating the precipitate of step (d).
Another aspect of the present disclosure relates to a method for preparing buprenorphine free base, comprising:
(a) heating a blend of an acetate salt of buprenorphine and an aqueous solution to provide precipitated buprenorphine free base; and
(b) filtering the blend of step (a).
Another aspect of the present disclosure relates to a method for preparing buprenorphine free base, comprising:
(a) mixing an acetate salt of buprenorphine in a solvent to form a blend;
(b) refluxing the blend at reflux temperature and removing acetate salt in the form of acetic acid in the vapor phase;
(c) cooling the blend to provide precipitated buprenorphine free base; and
(d) the buprenorphine free base is isolated.
Buprenorphine acetate hydrate or a composition containing buprenorphine acetate hydrate is suitable for use in the treatment or prevention of: pain, constipation, drug abuse, addictive disorders, emesis, respiratory depression or euphoria (hereinafter each a "condition").
Brief Description of Drawings
Figure 1 shows a schematic thermal ellipsoid of buprenorphine acetate tetrahydrate with selected hydrogen bonding.
Figure 2 shows a stack of buprenorphine acetate tetrahydrate in a unit cell.
Figure 3 shows a stick schematic of the components of the buprenorphine acetate tetrahydrate crystal, including the atomic numbering scheme used.
Figure 4 shows an X-ray powder diffraction ("XRPD") pattern of buprenorphine acetate tetrahydrate obtained using CuK α radiation.
Figure 5 shows a differential scanning calorimetry scan of buprenorphine acetate tetrahydrate at a heating rate of 10 ℃/min.
Figure 6 shows the determination of the integral ratio of the transition region in a differential scanning calorimetry scan of buprenorphine acetate tetrahydrate.
Detailed Description
The invention comprises the following:
(1) an acetate salt of buprenorphine.
(2) The acetate salt of buprenorphine of the above (1), which includes a hydrate.
(3) The acetate salt of buprenorphine of (2) above, wherein the hydrate comprises 1 to 6 water molecules per acetate molecule of the buprenorphine.
(4) The acetate salt of buprenorphine of the above (3), wherein the hydrate is a tetrahydrate.
(5) A purified acetate salt of buprenorphine of any one of (1) to (4) above.
(6) The purified acetate salt of buprenorphine of (5) above, which is a substantially pure acetate salt of buprenorphine.
(7) A crystalline form of the acetate salt of buprenorphine of any one of (1) to (6) above.
(8) One or more crystalline forms of the acetate salt of buprenorphine of (4).
(9) The crystalline form of (8) above, characterized by an X-ray powder diffraction pattern obtained by exposure to CuK α radiation comprising peaks at 2 θ angles substantially equal to at least the peaks at 16.21 and 18.70, and having at least one additional peak at 2 θ angle substantially equal to the peak at 8.77, 10.31, or 18.47.
(10) The crystalline form of (8) above, characterized by an X-ray powder diffraction pattern obtained by exposure to CuK α radiation comprising peaks at 2 θ angles substantially equal to at least the peaks at 8.77, 10.31, 16.21, 18.47, and 18.70, and having at least one additional peak at 2 θ angle substantially equal to the peak at 6.38, 11.93, or 19.40.
(11) The crystalline form of (8) above, characterized in that the X-ray powder diffraction pattern obtained by exposure to CuK α radiation comprises peaks at diffraction angles substantially equal to the peaks at least at those positions in the following table:
position 2 theta]
6.38
8.77
10.31
11.93
16.21
18.47
18.70
19.40
(12) The crystalline form of (8) above, which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in fig. 4 when measured using CuK α radiation.
(13) The crystalline form of any one of (8) to (12) above, wherein the crystalline form exhibits a first transition region having at least one peak position at about 50 ℃ to about 140 ℃, as measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute.
(14) The crystalline form of any one of (8) to (13) above, wherein the crystalline form exhibits a second transition region having a peak position at about 217 ℃ to about 225 ℃ as measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute.
(15) The crystalline form of (14) above, exhibiting an integral ratio of the first transition region at about 50 ℃ to about 140 ℃ relative to the second transition region at about 217 ℃ to about 225 ℃ of about 7 to about 8, wherein the integrals are determined over temperature ranges of about 35 ℃ to about 180 ℃ and about 203 ℃ to about 233 ℃, respectively.
(16) The crystalline form of (15) above, wherein the crystalline form exhibits an integral ratio of about 7.1 to about 7.8.
(17) The crystalline form of any one of (8) to (16) above, characterized in that it is a monoclinic crystal.
(18) The crystalline form of (17) above, wherein the unit cell parameter is
Figure BDA0001463758400000061
Figure BDA0001463758400000062
And is
Figure BDA0001463758400000063
(19) The crystalline form of (17) above, wherein the unit cell parameter is
Figure BDA0001463758400000064
Figure BDA0001463758400000065
And is
Figure BDA0001463758400000066
(20) The crystalline form of any one of (17) to (19) above, wherein the space group is P21。
(21) A pharmaceutical composition comprising the acetate salt of buprenorphine of any one of (1) to (6) above or the crystalline form of any one of (7) to (20) above, and a pharmaceutically acceptable carrier.
(22) A method for treating pain, constipation, substance abuse, addictive disorders, emesis, respiratory depression or euphoria comprising administering to an animal in need thereof an effective amount of the acetate salt of buprenorphine of any one of (1) to (6) above, the crystalline form of any one of (7) to (20) above, or the pharmaceutical composition of (21) above.
(23) A method for treating pain, comprising administering to an animal in need thereof an effective amount of the acetate salt of buprenorphine of any one of (1) to (6) above, the crystalline form of any one of (7) to (20) above, or the pharmaceutical composition of (21) above.
(24) A method for preparing an acetate salt of buprenorphine, comprising the steps of:
(a) contacting buprenorphine free base with a solution comprising acetic acid in a dissolution vessel to form a blend, wherein the blend is at a temperature of about 40 ℃ to about 80 ℃;
(b) optionally filtering the blend of step (a);
(c) adding a reagent to the blend produced in step (a) or (b) to precipitate the acetate salt of buprenorphine; and
(d) isolating the acetate salt of buprenorphine precipitated in step (c).
(25) The method of (24) above, wherein in step (a), the buprenorphine free base is contacted with from about 2 mass equivalents to about 6 mass equivalents of the solution comprising acetic acid relative to the starting mass of the free base.
(26) The method of (24) above, wherein the buprenorphine free base is contacted with from about 3 mass equivalents to about 5 mass equivalents of the solution comprising acetic acid relative to the starting mass of the free base.
(27) The method of any one of (24) to (26) above, wherein the solution comprising acetic acid is an aqueous solution.
(28) The method of (27) above, wherein the aqueous solution has about 40% to about 70% by weight of acetic acid relative to the weight of the aqueous solution.
(29) The method of (27) above, wherein the aqueous solution has about 45% to about 60% by weight of acetic acid relative to the weight of the aqueous solution.
(30) The method of any of (24) to (29) above, wherein in step (a), the admixture is at a temperature of from about 40 ℃ to about 80 ℃ for a period of time such that a substantial portion of the buprenorphine free base has dissolved.
(31) The method of (30) above, wherein in step (a), the admixture is at a temperature of from about 45 ℃ to about 75 ℃ for a period of time such that a substantial portion of the buprenorphine free base has dissolved.
(32) The method of (30) above, wherein in step (a) the admixture is at a temperature of from about 50 ℃ to about 70 ℃ for a period of time such that a substantial portion of the buprenorphine free base has dissolved.
(33) The method of any of (24) to (32) above, wherein in step (a), the admixture is agitated to accelerate dissolution of the buprenorphine free base.
(34) The method of (24) above, wherein the blend of step (a) is filtered in a filtration device in step (b).
(35) The method of (34) above, wherein in step (b), the blend of step (a) added to the filtration device is at a temperature of about 40 ℃ to about 80 ℃.
(36) The method of (34) above, wherein in step (b), the blend of step (a) added to the filtration device is at a temperature of about 45 ℃ to about 75 ℃.
(37) The method of any one of (34) to (36) above, wherein the dissolution vessel, the filtration device, or the dissolution vessel and the filtration device are flushed with an additional volume of a solution comprising acetic acid.
(38) The method of (37) above, wherein the additional volume of the solution comprising acetic acid is about 0.1 mass equivalents to about 2.0 mass equivalents relative to the starting mass of the buprenorphine free base in step (a).
(39) The method of (37) above, wherein the additional volume of the solution comprising acetic acid is about 0.3 mass equivalents to about 0.5 mass equivalents relative to the starting mass of the buprenorphine free base in step (a).
(40) The method of any one of (37) to (39) above, wherein the additional volume of the solution is an aqueous acetic acid solution.
(41) The method of (40) above, wherein the additional volume of the solution comprising acetic acid is an aqueous solution comprising acetic acid present at about 40 wt% to about 70 wt% relative to the weight of the solution.
(42) The method of any one of (24) to (41) above, wherein in step (c), the reagent is selected from the group consisting of an anti-solvent, seed crystals, and combinations thereof.
(43) The method of (42) above, wherein the reagent comprises an antisolvent.
(44) The method of (43) above, wherein the antisolvent comprises water.
(45) The process of (43) or (44) above, wherein about 0.2 mass equivalents to about 8.0 mass equivalents of antisolvent relative to the starting mass of free base in step (a) is added to the blend of step (a) or (b).
(46) The method of any one of (43) to (45) above, wherein the anti-solvent is added within about 10 ℃ of the temperature of the blend of step (a) or step (b).
(47) The method of (46) above, wherein the anti-solvent is added at a temperature within about 5 ℃ of the temperature of the blend of step (a) or step (b).
(48) The method of (42) above, wherein the reagent comprises seed crystals.
(49) The method of (48) above, wherein the seed crystals comprise an acetate salt of buprenorphine.
(50) The method of (49) above, wherein about 0.1% to about 5.0% by weight of seed crystals relative to the starting mass of the buprenorphine free base in step (a) are added to the blend of step (a) or (b).
(51) The method of any of (48) to (50) above, wherein the blend of step (a) or (b) is at a temperature of about 40 ℃ to about 80 ℃ when the seed crystals are added.
(52) The method of (51) above, wherein the blend of step (a) or (b) is at a temperature of about 55 ℃ to about 65 ℃ when the seed crystals are added.
(53) The method of (42) above, wherein a first amount of the antisolvent is added, followed by addition of the seed crystal.
(54) The method of (53) above, wherein said adding said seed crystals is followed by adding a second amount of said antisolvent.
(55) The method of (53) or (54) above, wherein the first amount of the antisolvent is about 0.2 mass equivalents to about 2.0 mass equivalents relative to the starting mass of the buprenorphine free base in step (a).
(56) The method of any of (53) to (55) above, wherein about 0.1 wt% to about 5.0 wt% of the seed crystals are added relative to the starting mass of the buprenorphine free base in step (a).
(57) The method of any of (54) to (56) above, wherein the second amount of anti-solvent is from about 1.0 mass equivalents to about 6.5 mass equivalents relative to the starting mass of the buprenorphine free base in step (a).
(58) The method of any of (24) to (57) above, further comprising cooling the admixture to a temperature of about 30 ℃ or less after adding the reagent and prior to isolating the acetate salt of buprenorphine in step (d).
(59) The method of any of (24) to (57) above, further comprising adding a co-solvent to the admixture after the precipitation of step (c) and prior to isolating the acetate salt of buprenorphine in step (d).
(60) The method of (59) above, wherein the co-solvent is selected from the group consisting of methanol, ethanol, isopropanol, and combinations thereof.
(61) The method of (59) above, wherein the co-solvent is isopropanol.
(62) The method of any of (59) to (61) above, further comprising cooling the blend to a temperature of about 30 ℃ or less after adding the co-solvent and prior to isolating the acetate salt of buprenorphine in step (d).
(63) The method of any one of (24) to (62) above, wherein the separation in step (d) is achieved by filtration.
(64) The method of any of (24) to (63) above, further comprising slurrying the acetate salt of the buprenorphine isolated from step (d) with a slurrying solution comprising water and an alcohol, and filtering the acetate salt therefrom.
(65) A buprenorphine acetate product obtained from the method of any one of (24) to (64) above.
(66) The product of (65) above, wherein the product comprises about 0.10% by weight or less of a compound of formula (10):
Figure BDA0001463758400000111
or a salt thereof.
(67) The product of (65) or (66) above, wherein the product comprises about 0.10% by weight or less of a compound of formula (11):
Figure BDA0001463758400000121
or a salt thereof.
(68) The product of any one of (65) to (67) above, wherein the product comprises about 0.10% by weight or less of a compound of formula (12):
Figure BDA0001463758400000122
or a salt thereof.
(69) The product of (68) above, wherein the product comprises about 0.08% by weight or less of an impurity represented by the compound of formula (12) or a salt thereof.
(70) The product of any one of (65) to (69) above, wherein the product comprises about 0.10 wt% or less of a compound of formula (14):
Figure BDA0001463758400000131
or a salt thereof.
(71) The product of any one of (65) to (70) above, wherein the product comprises about 0.10% by weight or less of a compound of formula (13):
Figure BDA0001463758400000132
or a salt thereof.
(72) The product of any one of (65) to (71) above, wherein the product comprises about 0.10% by weight or less of a compound of formula (15):
Figure BDA0001463758400000133
Figure BDA0001463758400000141
or a salt thereof.
(73) A pharmaceutical composition comprising the product of any one of (65) to (72) above and a pharmaceutically acceptable carrier.
(74) A method for treating pain, constipation, substance abuse, addictive disorders, emesis, respiratory depression or euphoria, comprising administering to an animal in need thereof an effective amount of the product of any one of (65) to (72) above or the pharmaceutical composition of (73) above.
(75) A method for treating pain, comprising administering to an animal in need thereof an effective amount of the product of any one of (65) to (72) above or the pharmaceutical composition of (73) above.
(76) A process for the preparation of buprenorphine free base, comprising the steps of:
(a) contacting an acetate salt of buprenorphine with the solution and a basic material to form a blend;
(b) agitating the admixture of step (a) at a temperature of about 20 ℃ to about 90 ℃ to provide buprenorphine free base;
(c) isolating the buprenorphine free base of step (b); and
(d) optionally repeating steps (a) to (c) one or more times.
(77) The method of (76) above, wherein in step (a) the acetate salt of buprenorphine is contacted with at least about 1 mass equivalent of the solution relative to the starting mass of the acetate salt in step (a).
(78) The method of (76) or (77) above, wherein the solution of step (a) comprises water and an alcohol.
(79) The method of (78) above, wherein the solution comprises about 30% to about 70% alcohol by weight in water.
(80) The method of (78) above, wherein the solution comprises about 40% to about 60% alcohol by weight in water.
(81) The method of any one of (78) to (80) above, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and combinations thereof.
(82) The method of (81) above, wherein the alcohol is isopropanol.
(83) The method of (76) above, wherein the basic material is selected from the group consisting of hydroxides, carbonates, alkoxides, hydrides, phosphates, borates, oxides, cyanides, silicates, amines, and combinations thereof.
(84) The method of (76) above, wherein the acetate salt of buprenorphine is contacted with from about 0.5 molar equivalents to about 20 molar equivalents of basic material relative to the starting moles of the acetate salt of buprenorphine in step (a).
(85) The method of (84) above, wherein the acetate salt of buprenorphine is contacted with from about 1 molar equivalent to about 10 molar equivalents of the basic material relative to the starting moles of acetate salt of buprenorphine in step (a).
(86) The method of any one of (76) to (85) above, wherein the admixture of step (a) is agitated in step (b) for about 1 hour to about 36 hours.
(87) The method of (86) above, wherein the agitating step (b) takes about 2 hours to about 8 hours.
(88) The method of (86) or (87) above, wherein in step (b), the blend is agitated at a temperature of about 25 ℃ to about 90 ℃.
(89) The method of (88) above, wherein in step (b), the admixture is agitated at a temperature of about 30 ℃ to about 45 ℃.
(90) The method of any one of (76) to (89) above, wherein the separating in step (c) is achieved by filtration.
(91) The method of any of (76) to (90) above, further comprising the step of slurrying the buprenorphine free base of step (c) with a slurrying solution comprising water and an alcohol, and filtering the free base therefrom.
(92) A buprenorphine free base product obtained from the method of any one of (76) to (91) above.
(93) The product of (92) above, wherein the product comprises about 0.10% by weight or less of a compound of formula (10):
Figure BDA0001463758400000161
(94) the product of (92) or (93) above, wherein the product comprises about 0.10% by weight or less of a compound of formula (11):
Figure BDA0001463758400000162
(95) the product of any of (92) to (94) above, wherein the product comprises about 0.10 wt% or less of a compound of formula (12):
Figure BDA0001463758400000171
(96) the product of (95) above, wherein said product comprises about 0.08 wt% or less of said impurity represented by compound of formula (12).
(97) The product of any of (92) to (96) above, wherein the product comprises about 0.10% by weight or less of a compound of formula (14):
Figure BDA0001463758400000172
(98) the product of any of (92) to (97) above, wherein the product comprises about 0.10 wt% or less of a compound of formula (13):
Figure BDA0001463758400000173
Figure BDA0001463758400000181
(99) the product of any of (92) to (98) above, wherein the product comprises about 0.10 wt% or less of a compound of formula (15):
Figure BDA0001463758400000182
(100) a pharmaceutical composition comprising the product of any one of (92) to (99) above and a pharmaceutically acceptable carrier.
(101) A method for treating pain, constipation, substance abuse, addictive disorders, emesis, respiratory depression or euphoria, comprising administering to an animal in need thereof an effective amount of the product of any one of (92) to (99) above or the pharmaceutical composition of (100) above.
(102) A method for treating pain, the method comprising administering to an animal in need thereof an effective amount of the product of any one of (92) to (99) above or the pharmaceutical composition of (100) above.
(103) A method for the preparation of buprenorphine free base, the method comprising treating an acetate salt of buprenorphine at a pressure, temperature and for a period of time sufficient to remove acetic acid.
(104) The method of (103) above, wherein the pressure is a sub-atmospheric pressure of about 100 torr to about 200 torr.
(105) The method of (104) above, wherein the temperature is at least about 30 ℃ and the time is at least about 1 hour.
(106) The method of (105) above, wherein the temperature is at least about 50 ℃.
(107) The method of (105) above, wherein the temperature is at least about 65 ℃.
(108) The method of any of (103) to (107) above, wherein the treating lasts at least about 5 hours.
(109) The method of (108) above, wherein the treating lasts at least about 10 hours.
(110) The method of any of (103) to (109) above, further comprising slurrying the buprenorphine free base with a slurrying solution comprising water and an alcohol, and filtering the free base therefrom.
(111) The method of (103) above, wherein the pressure is an atmospheric pressure of about 620 torr to about 780 torr.
(112) The method of (111) above, wherein the temperature is from about 65 ℃ to about 100 ℃.
(113) The method of (111) or (112) above, wherein the treating lasts at least about 7 hours.
(114) The method of any of (111) to (113) above, wherein the treating is continued long enough to form substantially pure buprenorphine free base.
(115) The method of any of (103) to (114) above, wherein the acetic acid in the final buprenorphine free base product is present at less than about 0.5% by weight.
(116) A buprenorphine free base product obtained from the method of any one of (103) to (115) above.
(117) A pharmaceutical composition comprising the product of (116) above and a pharmaceutically acceptable carrier.
(118) A method for treating pain, constipation, substance abuse, addictive disorders, emesis, respiratory depression or euphoria comprising administering to an animal in need thereof an effective amount of the product of (116) above or the pharmaceutical composition of (117) above.
(119) A method for treating pain, comprising administering to an animal in need thereof an effective amount of the product of (116) above or the pharmaceutical composition of (117) above.
(120) A process for the preparation of buprenorphine free base, comprising the steps of:
(a) dissolving an acetate salt of buprenorphine in a solution to form a blend;
(b) optionally filtering the blend of step (a);
(c) adding a basic material to the blend in step (a) or (b) to form a second blend;
(d) adding an anti-solvent to the second admixture produced in step (c) to form a precipitate of the buprenorphine free base; and
(e) isolating the precipitate of step (d).
(121) The method of (120) above, wherein the solution of step (a) comprises an organic solvent.
(122) The method of (121) above, wherein the organic solvent comprises an alcohol.
(123) The method of (122) above, wherein the organic solvent comprises an alcohol selected from the group consisting of methanol, ethanol, and isopropanol.
(124) The method of any one of (120) to (123) above, wherein the antisolvent of step (d) comprises an aqueous solution.
(125) The method of any of (120) to (124) above, wherein the acetate salt of buprenorphine is contacted with at least about 3 mass equivalents of the solution relative to the starting mass of the acetate salt of buprenorphine in step (a).
(126) The method of any of (120) to (125) above, further comprising mixing the admixture of step (a) at a temperature of about 20 ℃ to about 90 ℃ such that substantially all of the acetate salt of buprenorphine is dissolved.
(127) The method of (126) above, wherein in step (a), the blend is at a temperature of at least about 40 ℃.
(128) The method of (126) above, wherein in step (a), the blend is at a temperature of at least about 50 ℃.
(129) The method of any one of (120) to (128) above, wherein the blend of step (a) is filtered in step (b).
(130) The method of any of (120) to (129) above, wherein in step (c), from about 1.0 molar equivalents to about 20 molar equivalents of base, relative to the starting moles of acetate salt of buprenorphine in step (a), is added to the blend produced in step (a) or (b).
(131) The method of any of (120) to (130) above, wherein in step (d), at least about 3 mass equivalents of the anti-solvent relative to the starting mass of the acetate salt of buprenorphine in step (a) is added to the second blend produced in step (c).
(132) The method of any one of (120) to (131) above, wherein the separating in step (e) is achieved by filtration.
(133) The method of any one of (120) to (132) above, further comprising slurrying the isolated free base obtained from step (e) with a slurrying solution comprising water and an alcohol, and filtering the free base therefrom.
(134) A buprenorphine free base product obtained from the method of any one of (120) to (133) above.
(135) The product of (134) above, wherein the product comprises about 0.10 wt% or less of a compound of formula (10):
Figure BDA0001463758400000221
(136) the product of (134) or (135) above, wherein the product comprises about 0.10% by weight or less of a compound of formula (11):
Figure BDA0001463758400000222
(137) the product of any of (134) to (136) above, wherein the product comprises about 0.10 wt% or less of a compound of formula (12):
Figure BDA0001463758400000223
(138) the product of (137) above, wherein the product comprises about 0.08 wt% or less of the compound of formula (12).
(139) The product of any of (134) to (138) above, wherein the product comprises about 0.10 wt% or less of a compound of formula (14):
Figure BDA0001463758400000231
(140) the product of any of (134) to (139) above, wherein the product comprises about 0.10 wt% or less of a compound of formula (13):
Figure BDA0001463758400000232
(141) the product of any of (134) to (140) above, wherein the product comprises about 0.10 wt% or less of a compound of formula (15):
Figure BDA0001463758400000241
(142) a pharmaceutical composition comprising the product of any one of (134) to (141) above and a pharmaceutically acceptable carrier.
(143) A method for treating pain, constipation, substance abuse, addictive disorders, emesis, respiratory depression or euphoria, comprising administering to an animal in need thereof an effective amount of the product of any one of (134) to (141) above or the pharmaceutical composition of (142) above.
(144) A method for treating pain, comprising administering to an animal in need thereof an effective amount of the product of any one of (134) to (131) above or the pharmaceutical composition of (142) above.
(145) A process for the preparation of buprenorphine free base, the process comprising:
(a) heating a blend of an acetate salt of buprenorphine and an aqueous solution to provide precipitated buprenorphine free base; and
(b) filtering the blend of step (a).
(146) The method of (145) above, wherein the aqueous solution consists essentially of water.
(147) The method of (145) above, wherein the aqueous solution comprises a mixture of water and an alcohol.
(148) The method of (147) above, wherein the alcohol is isopropanol.
(149) The method of any of (145) to (148) above, wherein the heating reaches a temperature of about 70 ℃ to about 90 ℃.
(150) The method of (145) or (146) above, further comprising washing the solid filtered product of step (b) with a second aqueous solution.
(151) The method of any one of (145) to (150) above, further comprising the step of drying the solid filtered product of step (b).
(152) A buprenorphine free base product obtained from the method of any one of (145) to (151) above.
(153) A pharmaceutical composition comprising the product of (152) above and a pharmaceutically acceptable carrier.
(154) A method for treating pain, constipation, substance abuse, addictive disorders, emesis, respiratory depression or euphoria comprising administering to an animal in need thereof an effective amount of the product of (152) above or the pharmaceutical composition of (153) above.
(155) A method for treating pain, comprising administering to an animal in need thereof an effective amount of the product of (152) above or the pharmaceutical composition of (153) above.
(156) A process for the preparation of buprenorphine free base, the process comprising:
(a) mixing an acetate salt of buprenorphine in a solvent to form a blend;
(b) refluxing the blend at reflux temperature and removing the acetate salt in the form of acetic acid in the vapor phase;
(c) cooling the blend to provide precipitated buprenorphine free base; and
(d) isolating the buprenorphine free base.
(157) The method of (156) above, wherein the isolating of step (d) comprises filtering the precipitated buprenorphine free base of step (c).
(158) The method of (156) or (157) above, wherein the solvent comprises an organic solvent.
(159) The method of (158) above, wherein the organic solvent comprises heptane.
(160) A buprenorphine free base product obtained from the method of any one of (156) to (159) above.
(161) A pharmaceutical composition comprising the product of (160) above and a pharmaceutically acceptable carrier.
(162) A method for treating pain, constipation, substance abuse, addictive disorders, emesis, respiratory depression or euphoria comprising administering to an animal in need thereof an effective amount of the product of (160) above or the pharmaceutical composition of (161) above.
(163) A method for treating pain, comprising administering to an animal in need thereof an effective amount of the product of (160) above or the pharmaceutical composition of (161) above.
4.1 definition
As used herein, the following terms are intended to have the following meanings.
As used herein, "crystalline form" refers to anhydrous crystalline forms, partially crystalline forms, mixtures of crystalline forms, hydrate crystalline forms, and solvate crystalline forms.
As used herein, "polymorph," "polymorph," and related terms refer to two or more crystal forms consisting essentially of the same molecules and/or ions and include (but are not limited to) other solid state molecular forms, such as hydrates and solvates. Different polymorphs can have different physical properties such as melting temperature, heat of fusion, solubility characteristics, and/or vibrational spectra due to the arrangement or conformation of molecules and/or ions in the crystal lattice. Differences in physical properties may affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacture) and dissolution rate (an important factor in bioavailability).
As used herein, "solvate" refers to a crystalline form of a compound, molecule, atom, ion, or salt thereof, which further contains a solvent molecule incorporated into the crystalline structure. The solvent molecules in the solvate may be present in a regular arrangement or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric amount of solvent molecules. For example, solvates with non-stoichiometric amounts of solvent molecules may result from partial solvent loss of the solvate.
As used herein, "hydrate" refers to a crystalline form of a compound, molecule, atom, ion, or salt thereof, which further contains one or more water molecules in a three-dimensional arrangement. It may comprise non-stoichiometric hydrates or stoichiometric hydrates such as hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate or hexahydrate, or hydrates in which the ratio of water/compound or salt thereof need not be an integer but is, for example, any value in the range 0.5 to 10.0. In some embodiments, the hydrate has a water/compound or salt thereof ratio of 1 to 8. In some embodiments, the hydrate has a water/compound or salt thereof ratio of 1 to 5. In some embodiments, the hydrate has a water/compound or salt thereof ratio of 3 to 5, e.g., 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.
"anhydrous," "anhydrate," and related terms refer to compounds, molecules, atoms, ions, or salts that are anhydrous or substantially anhydrous. In some embodiments, "anhydrous" or "anhydrate" refers to a water content of less than about 1.0 wt.% water by weight.
As used herein, "blend" refers to a combination of elements of a mixture, regardless of the phase of the combination (e.g., entirely liquid or slurry or both liquid and solid).
As used herein, "seeding" refers to adding a crystalline material to a blend (e.g., a solution) to initiate recrystallization or crystallization.
As used herein, "anti-solvent" refers to a solvent or liquid in which a compound is poorly soluble to insoluble. Antisolvents may be used, for example, to precipitate dissolved compounds from solution. One example of an anti-solvent may be water (see example 2).
As used herein, "purified" with respect to a compound or composition means the purity of the specified compound. For example, a given compound is "purified" when the compound is the major component of the composition, i.e., comprises at least 50% by weight of the formulation. Thus, "purified" encompasses at least about 50 wt.%, at least about 60 wt.%, at least about 65 wt.%, at least about 70 wt.%, at least about 75 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 92 wt.%, at least about 94 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 98.5 wt.%, at least about 99.0 wt.%, or at least about 99.5 wt.% of the formulation as the compound of interest.
As used herein with respect to a compound or composition, "substantially pure" means that at least 98% by weight of the formulation is the subject compound. In some embodiments, a compound or composition is "substantially purer" when at least 99% by weight of the formulation is the subject compound.
With respect to a first compound or a composition containing a first compound, "substantially free" of another compound as used herein means that the other compound is present in an amount of no more than 1% by weight of the amount of the target first compound.
As used herein, "crystallization" and related terms refer to the process of forming solid crystals that precipitate from a solution, wherein "crystals" refers to a solid material in which the constituent compounds, salts or solvates thereof are arranged in a regular form extending in all three spatial dimensions.
As used herein, "Precipitating", "precipitation" and related terms encompass "crystallizing", and "crystallization", unless otherwise specified. In some embodiments, the precipitate described herein is anhydrous. In some embodiments, the precipitate is a mixture of anhydrous and crystalline components. In some embodiments, the precipitate described herein is crystalline.
As used herein, "critical amount," "threshold value," and related terms refer to the reported, identified, and allowable limits for impurities, particularly organic impurities, in bulk drugs and dosage forms as set forth in the latest version of the ICH guide or by regulatory agencies such as the U.S. food and drug administration ("FDA") and the european drug administration ("EMA"), and are available from the latest version of the FDA or EMA monograph.
"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to a human or animal without excessive toxicity, irritation, allergic response, or other problem complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "salt" refers to a compound comprising at least one anion (e.g., the anion of acetic acid) and at least one cation (e.g., the cation of buprenorphine resulting from protonation of the buprenorphine free base by a bronsted acid (e.g., phosphoric acid)). The salt may be the result of a neutralization reaction between an acid and a base (e.g., a bronsted acid and a bronsted base, or a lewis acid and a lewis base). In its solid form, the salt may be formed by precipitation or may have a crystalline structure. The term "salt" encompasses all salts of the disclosed compounds.
"drug" as used hereinBy "pharmaceutically acceptable salt" is meant any pharmaceutically acceptable salt that can be prepared from the compound or by the methods of the present disclosure, including salts formed from acid and base functional groups, such as the nitrogen group of buprenorphine. Illustrative salts include, but are not limited to, sulfate, citrate, acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinic acid, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)). The term "pharmaceutically acceptable salts" also includes salts prepared from compounds having acidic functional groups (such as carboxylic acid functional groups) and pharmaceutically acceptable inorganic or organic bases. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, cesium and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia and organic amines such as unsubstituted or hydroxy-substituted monoalkylamines, dialkylamines or trialkylamines; dicyclohexylamine; tributylamine; pyridine; picoline; N-methyl-N-ethylamine; diethylamine; triethylamine; mono- (2-hydroxy- (C)1-C3) Alkylamine), bis- (2-hydroxy- (C)1-C3) Alkylamine) or tris- (2-hydroxy- (C)1-C3) Alkylamines) such as mono- (2-hydroxyethyl) amine, bis- (2-hydroxyethyl) amine or tris- (2-hydroxyethyl) amine, 2-hydroxy-tributylamine or tris- (hydroxymethyl) methylamine; n, N-bis- [ (C)1-C3) Alkyl radical]-N- (hydroxy- (C)1-C3) Alkyl) -amines such as N, N-dimethyl-N- (2-hydroxyethyl) amine or tris- (2-hydroxyethyl) amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.
In some embodiments, the pharmaceutically acceptable salt is a hydrochloride, levulinate, sulfate, acetate, sodium salt, potassium salt, benzenesulfonate, p-toluenesulfonate, or fumarate salt. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride, levulinate, acetate or sulfate salt. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a levulinate salt. In some embodiments, the pharmaceutically acceptable salt is an acetate salt. In some embodiments, the pharmaceutically acceptable salt is a sulfate salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the pharmaceutically acceptable salt is a potassium salt. In some embodiments, the pharmaceutically acceptable salt is p-toluenesulfonate. Various pharmaceutically acceptable salts can be prepared according to the teachings of the present disclosure by reacting the compound with an appropriate acid or by any of a variety of known methods in view of the present disclosure.
An "effective amount" as used herein with respect to a therapeutic agent refers to an amount of an agent or compound of the present disclosure administered to an animal that provides a therapeutic effect.
As used herein, "Treatment of," "treating," and related terms include ameliorating, reducing, slowing, or terminating a condition or a symptom thereof by administering an effective amount of an agent or compound of the present disclosure. In some embodiments, treating comprises inhibiting, e.g., reducing, the overall frequency of onset of the condition or symptoms thereof.
As used herein, "Prevention" (Prevention of), "Prevention" and related terms include avoiding the onset of the condition or symptoms thereof by administering an effective amount of an agent or compound of the present disclosure.
As used herein, "disorder" includes, but is not limited to, the conditions defined herein.
As used herein, "animal" includes, but is not limited to, a human or non-human animal, such as a companion or livestock animal, e.g., a cow, monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig. In one embodiment, the animal is a human.
The term "Cmax"meansMaximum plasma concentrations obtained during the dosing interval.
The term "bioavailability" is defined for purposes of this disclosure as the relative degree of absorption of a drug (e.g., buprenorphine) from a dosage form (e.g., unit dosage form). Bioavailability is also referred to as "AUC" (i.e., the area under the plasma concentration versus time curve).
The term "molar equivalent" is defined for purposes of this disclosure as the number of moles of "X" relative to the number of moles of "Y". For example, 5 molar equivalents of X relative to Y means that if 1 mole of Y is used, 5 moles of X are used. 1 molar equivalent of X relative to Y means that if 1 mole of Y is used, 1 mole of X is used.
The term "mass equivalent" is defined for purposes of this disclosure as the mass amount of "X" relative to the mass amount of "Y". For example, X of 4 mass equivalents relative to Y means that if 1g Y is used, then 4g X is used. With respect to Y, 1 mass equivalent of X means that if 1kg of Y is used, 1kg of X is used.
The articles "a" and "the" as used herein mean one or more than one of the substance specified by the term after the article, unless the context clearly indicates otherwise. For example, a "compound of formula (1)" encompasses one or more molecules of the compound of formula (1).
Chemical structures predominate in case of doubt as to the identity of the chemical structures and chemical names depicted.
It is to be understood that various features of the disclosure which are, for clarity, described in the context of separate embodiments may also be provided in combination in a single embodiment, unless specifically excluded herein. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately and/or in any suitable subcombination unless specifically excluded herein.
4.2 buprenorphine acetate and corresponding hydrates
In some aspects, the present disclosure provides novel salts of buprenorphine. In particular, the novel salts of the present disclosure exhibit superior properties and characteristics relative to other known salts of buprenorphine, for example as disclosed in example 1 herein. In particular, the present disclosure provides acetate salts of buprenorphine. Buprenorphine, namely (4R, 4aS, 6R, 7aR, 12bS) -3- (cyclopropylmethyl) -6- ((S) -2-hydroxy-3, 3-dimethylbut-2-yl) -7-methoxy-1, 2,3, 4,5, 6, 7,7 a-octahydro-4 a, 7-ethano-4, 12-methanobenzofuran [3, 2-e ] isoquinolin-9-ol, has the chemical structure of formula (1):
Figure BDA0001463758400000321
the monoacetate of buprenorphine can be depicted as shown in formula (1 a):
Figure BDA0001463758400000322
in some embodiments, the present disclosure provides polymorphs of the acetate salt of formula (1 a). In some embodiments, the polymorph of the acetate salt of formula (1a) can be an anhydrate, solvate or hydrate.
In some embodiments, the acetate salt of buprenorphine is a hydrate comprising 1 to 6 water molecules per acetate molecule. In some embodiments, each acetate salt of formula (1a) may be associated with 1, 2,3, 4,5, or 6 water molecules. In particular embodiments, each acetate salt of formula (1a) is associated with 4 water molecules and is referred to herein as a tetrahydrate, which may be depicted by formula (1 b):
Figure BDA0001463758400000331
in some embodiments, the stoichiometry of buprenorphine acetate molecules to water molecules is calculated as an average for a given sample. For example, for a given sample of buprenorphine acetate hydrate, the stoichiometry averages about 4 water molecules per buprenorphine acetate molecule. In some embodiments, the buprenorphine acetate hydrate has an average of about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5 water molecules per buprenorphine acetate molecule.
In some embodiments, the buprenorphine acetate is in an anhydrous form. In some embodiments, the buprenorphine acetate anhydrate is "substantially free" of water. A substantially water-free formulation may have an average stoichiometry of less than 0.40 water molecules, such as about 0.30 water molecules or less, about 0.20 water molecules or less, about 0.10 water molecules or less, about 0.05 water molecules or less, about 0.02 water molecules or less, or about 0.01 water molecules or less per buprenorphine acetate molecule. In some embodiments, the substantially water-free buprenorphine acetate anhydrate has less than about 1.0%, less than about 0.7%, less than about 0.5%, less than about 0.4%, or less than about 0.2% water by weight.
In some embodiments, the buprenorphine acetate is in the form of purified buprenorphine acetate. In some embodiments, the purified buprenorphine acetate is at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 92%, at least about 94%, at least about 96%, or at least about 97% by weight of the formulation. In some embodiments, the buprenorphine acetate is in the form of substantially pure buprenorphine acetate as defined herein, e.g., at least about 98% or in another embodiment at least about 98.5% by weight of the formulation. In some embodiments, the buprenorphine acetate is in the form of a substantially more pure buprenorphine acetate as defined herein, e.g., at least about 99.0 wt% or in another embodiment at least about 99.5 wt% of the weight of the formulation.
In some embodiments, the buprenorphine acetate of the present disclosure is a crystalline form of buprenorphine acetate, such as an anhydrate, hydrate or solvate of buprenorphine acetate. In some embodiments, the buprenorphine acetate is a crystalline form of a hydrate of buprenorphine acetate, where the hydrate may have a number of water molecules per acetate molecule, such as 1, 2,3, 4,5, or 6 water molecules per acetate molecule. In some embodiments, the crystalline form is the tetrahydrate depicted in formula (1b) shown above.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by an X-ray powder diffraction ("XRPD") pattern obtained using cuka radiation, the pattern comprising one or more peaks at diffraction angles substantially equal to those in table 1.
TABLE 1
Position 2 theta] Relative intensity [% ]]
6.38 10
8.77 32
10.31 24
11.93 19
16.21 100
18.47 25
18.70 53
19.40 14
In some embodiments, the crystalline form of buprenorphine acetate is characterized by an XRPD pattern obtained using cuka radiation, the pattern comprising one or more peaks at 2 Θ angles substantially equal to 6.38, 8.77, 10.31, 11.93, 16.21, 18.47, 18.70, and 19.40. In some embodiments, the crystalline form of buprenorphine acetate is characterized by an XRPD pattern obtained using cuka radiation that includes peaks at 2 Θ angles that are substantially equal to at least the peaks at 16.21 and 18.70, and has at least one additional peak at 2 Θ angles that is substantially equal to at least one of the peaks at 8.77, 10.31, or 18.47. In some embodiments, the crystalline form of buprenorphine acetate is characterized by an XRPD pattern obtained using cuka radiation that includes peaks at 2 Θ angles that are substantially equal to at least the peaks at 16.21 and 18.70, and has at least two additional peaks at 2 Θ angles that are substantially equal to at least two of the peaks at 8.77, 10.31, or 18.47. In some embodiments, the crystalline form of buprenorphine acetate is characterized by an XRPD pattern obtained using cuka radiation that includes peaks at 2 Θ angles that are substantially equal to at least the peaks at 8.77, 10.31, 16.21, 18.47, and 18.70.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by an XRPD pattern obtained using cuka radiation that includes peaks at 2 Θ angles that are substantially equal to at least the peaks at 8.77, 10.31, 16.21, 18.47, and 18.70, and has at least one additional peak at 2 Θ angles that is substantially equal to at least one of the peaks at 6.38, 11.93, or 19.40. In some embodiments, the crystalline form of buprenorphine acetate is characterized by an XRPD pattern obtained using cuka radiation that includes peaks at 2 Θ angles that are substantially equal to at least the peaks at 8.77, 10.31, 16.21, 18.47, and 18.70, and has at least two additional peaks at 2 Θ angles that are substantially equal to at least two of the peaks at 6.38, 11.93, or 19.40. In some embodiments, the crystalline form of buprenorphine acetate is characterized by an XRPD pattern obtained using cuka radiation that includes peaks at 2 Θ angles that are substantially equal to at least the peaks at 6.38, 8.77, 10.31, 11.93, 16.21, 18.47, 18.70, and 19.40.
It will be appreciated that different equipment and/or conditions may result in slightly different XRPD data being generated. For example, there may be a change in the position and/or relative intensity of the peaks. In particular, the intensity of the XRPD peaks may vary due to particle size and shape due to the stacking effect of the crystalline particles in the XRPD peaks. Such stack effects are known in the art and are commonly referred to as "preferred orientation" effects. The preferred orientation in the sample affects the intensities of the multiple XRPD peaks such that some peaks are stronger and others are less strong than would be expected from a completely random sample. XRPD intensity variations can occur due to different particle sizes and shapes. It is also recognized in the art that the location of the XRPD peaks is affected by the exact height of the sample in the diffractometer and the zero calibration of the diffractometer. The surface flatness of the sample may also have a minor effect. Thus, the presented XRPD data should not be considered as absolute values.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by an XRPD pattern obtained using cuka radiation that is substantially the same as the XRPD pattern shown in figure 4. If the first XRPD peak has an angle of 2 θ within 0.2 ° of the second XRPD peak, the first peak is considered to have the same angle of 2 θ as the second peak, i.e., the first peak is substantially equal to the second peak.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by a differential scanning calorimetry ("DSC") transition curve. DSC measures the heat flow of a sample as a function of temperature, with a typical heating rate (i.e., temperature change) of about 10 ℃/min. In some embodiments, the crystalline form of buprenorphine acetate is characterized by a transition having at least one peak position at about 50 ℃ to about 180 ℃, or about 50 ℃ to about 140 ℃, or about 80 ℃ to about 130 ℃, or about 90 ℃ to about 120 ℃, or about 95 ℃ to about 115 ℃, as measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by a transition having a peak position at about 217 ℃ to about 225 ℃, or about 218 ℃ to about 223 ℃, or about 219 ℃ to about 223 ℃, as measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by a transition having at least one peak position at about 50 ℃ to about 180 ℃, or about 50 ℃ to about 140 ℃, or about 80 ℃ to about 130 ℃, or about 90 ℃ to about 120 ℃, or about 95 ℃ to about 115 ℃ and another transition having a peak position at about 210 ℃ to about 225 ℃, or about 217 ℃ to about 225 ℃, or about 218 ℃ to about 223 ℃, or about 219 ℃ to about 223 ℃, as measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by a first transition region (region 1) having at least one peak with a peak position at about 50 ℃ to about 180 ℃, and a second transition region (region 2) having a peak with a peak position at about 210 ℃ to about 225 ℃, as discussed above and as measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by a DSC curve that is substantially the same as the DSC curve shown in figure 5, when measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute. In some embodiments, the crystalline form of buprenorphine acetate is characterized by a DSC curve that is substantially the same as the DSC curve shown in figure 6, when measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by an integrated (area under the curve) ratio of the first transition region (region 1) to the second transition region (region 2), i.e., region 1/region 2, of about 7.0 to about 8.0. In some embodiments, the approximate integral ratio of region 1/region 2 for buprenorphine acetate is from about 7.1 to about 7.9. In some embodiments, the approximate integral ratio of region 1/region 2 for buprenorphine acetate is from about 7.1 to about 7.7. In some embodiments, the integral value for the transition region is determined over a temperature range of about 35 ℃ to about 180 ℃ for the first transition region (region 1) and about 203 ℃ to about 233 ℃ for the second transition region (region 2).
In some embodiments, the crystalline form of buprenorphine acetate is characterized by a water content of about 11.1% to about 13.0%, or about 11.5% to about 12.6%, or about 11.8% to about 12.5%, or about 12.0% to about 12.3% by weight, as measured by Karl Fischer titration. In some embodiments, the crystalline form of buprenorphine acetate is characterized by a water content of about 12.3%, about 12.25%, or about 12.0% by weight. In some embodiments, the foregoing water content is for buprenorphine acetate tetrahydrate, the compound of formula (1 b).
In some embodiments, the crystalline form of buprenorphine acetate is characterized by one or more of the following:
(1) at least one of the XRPD peaks 2 Θ shown in table 1;
(2) an XRPD pattern substantially similar to that of figure 4;
(3) a DSC profile substantially similar to figure 5 or figure 6;
(4) a DSC integral ratio of transition region 1/region 2 of about 7.0 to about 8.0; and
(5) a water content of about 11.1 wt% to about 13.0 wt%.
In some embodiments, the crystalline form of buprenorphine acetate is characterized by two, three, four, or all of the above features (1) to (5).
In some embodiments, the crystalline form of buprenorphine acetate is characterized as a monoclinic crystal, such as described in the crystal characterization data presented in table 4 below. In some embodiments, the crystalline form is characterized by a monoclinic space group P21. In some embodiments, the crystalline form has a unit cellParameter is
Figure BDA0001463758400000381
Figure BDA0001463758400000382
And is
Figure BDA0001463758400000383
In some embodiments, the crystalline form has a unit cell parameter of
Figure BDA0001463758400000384
And is
Figure BDA0001463758400000385
Figure BDA0001463758400000386
In some embodiments, the crystalline form of buprenorphine acetate is space group P21Has a unit cell parameter of
Figure BDA0001463758400000387
Figure BDA0001463758400000388
And is
Figure BDA0001463758400000389
In some embodiments, the crystalline form of buprenorphine acetate is space group P21Has a unit cell parameter of
Figure BDA00014637584000003810
Figure BDA00014637584000003811
And is
Figure BDA00014637584000003812
In some embodiments, the crystalline form of buprenorphine acetate is a crystalline form of buprenorphine acetateHaving the same or equivalent atomic fraction coordinates set forth in Table 5 (× 10)4) And equal isotropic displacement parameter
Figure BDA00014637584000003813
In some embodiments, the buprenorphine acetate salt and polymorphs thereof exhibit high stability. In some embodiments, the buprenorphine acetate salt and polymorphs thereof retain a purity of about 95.0 area% or greater, a purity of about 96.0 area% or greater, a purity of about 97.0 area% or greater, a purity of about 98.0 area% or greater, a purity of about 98.5 area% or greater, a purity of about 99.0 area% or greater, a purity of about 99.1 area% or greater, a purity of about 99.2 area% or greater, a purity of about 99.3 area% or greater, a purity of about 99.4 area% or greater, a purity of about 99.5 area% or greater, a purity of about 99.6 area% or greater, a purity of about 99.7 area% or greater, a purity of about 99.8 area% or greater, or a purity of about 99.9 area% or greater under long-term stability conditions (i.e., 25 ℃ at 65% relative humidity). In some embodiments, the buprenorphine acetate salt and polymorphs thereof retain a purity of about 95.0 area% or greater, a purity of about 96.0 area% or greater, a purity of about 97.0 area% or greater, a purity of about 98.0 area% or greater, a purity of about 98.5 area% or greater, a purity of about 99.0 area% or greater, a purity of about 99.1 area% or greater, a purity of about 99.2 area% or greater, a purity of about 99.3 area% or greater, a purity of about 99.4 area% or greater, a purity of about 99.5 area% or greater, a purity of about 99.6 area% or greater, a purity of about 99.7 area% or greater, a purity of about 99.8 area% or greater, or a purity of about 99.9 area% or greater under accelerated stability conditions (i.e., 40 ℃ at 75% relative humidity). (see example 7 below for a method of determining area% impurities under stability test conditions). In general, to be considered unaffected by moisture, ICH guidelines and the united states pharmacopoeia and EMA monograph require that a pharmaceutical compound should be stable at 75% RH ± 5% ("RH" ═ relative humidity) under accelerated storage conditions of 40 ℃ ± 2 ℃ for a minimum period of 6 months and under long-term (i.e. minimum period of 12 months) storage conditions of 25 ℃ ± 2 ℃ at 60% RH ± 5% or 30 ℃ ± 2 ℃ at 65% RH ± 5%.
In some embodiments, the buprenorphine acetate salt and polymorphs thereof exhibit high photostability. In some embodiments, buprenorphine acetate and polymorphs thereof, when exposed to sustained UV light (e.g., from at 21.9W/m)2UV light from TL20W/12RS UV bulb (Philips Lighting) below) retained about 99.0 area% or greater purity, about 99.1 area% or greater purity, about 99.2 area% or greater purity, about 99.3 area% or greater purity, about 99.4 area% or greater purity, about 99.5 area% or greater purity, about 99.6 area% or greater purity, about 99.7 area% or greater purity, about 99.8 area% or greater purity, or about 99.9 area% or greater purity for up to 3 months. In some embodiments, the buprenorphine acetate salt and polymorphic forms thereof retain about 99.0 area% or greater purity, about 99.1 area% or greater purity, about 99.2 area% or greater purity, about 99.3 area% or greater purity, about 99.4 area% or greater purity, about 99.5 area% or greater purity, about 99.6 area% or greater purity, about 99.7 area% or greater purity, about 99.8 area% or greater purity, or about 99.9 area% or greater purity when exposed to visible light (e.g., visible light from F24T12/CW/HO fluorescent bulbs (Philips Lighting) at 27K lux) for up to 3 months.
It has been found that the identity of impurities present or absent in the buprenorphine acetate salts of the present disclosure is the same as the identity of impurities present or absent in the buprenorphine free base prepared from the buprenorphine acetate salt. For example, if a compound of formula (12) (see section 4.3) is present in the buprenorphine acetate of the present disclosure, and a compound of formula (18) (see section 4.3) is absent therein, then the compound of formula (12) will be present in the buprenorphine free base prepared from that buprenorphine acetate, and the compound of formula (18) will be absent therein. It has also been found that the amount of each impurity present in the buprenorphine acetate of the present disclosure is about the same as the amount of that impurity present in the buprenorphine free base prepared from the buprenorphine acetate. For example, if 0.080% of the compound of formula (12) is present in the buprenorphine acetate of the present disclosure, about 0.080% (± 20%, i.e., about 0.064% to about 0.096%) of the compound of formula (12) will be present in the buprenorphine free base prepared from the buprenorphine acetate. Thus, characterization of the identity and amount of one or more impurities in the buprenorphine acetate of the present disclosure also generally provides impurity characterization with respect to the buprenorphine free base prepared from the buprenorphine acetate, and vice versa.
4.3 methods for preparing buprenorphine acetate and buprenorphine acetate prepared by said methods
In another aspect, the present disclosure provides a method for preparing very pure buprenorphine acetate. In a surprising discovery of the present disclosure, the buprenorphine acetate salt prepared by the procedure described below provides an intermediate via which very high purity buprenorphine, substantially free of impurities, can be obtained in very high yields under relatively mild conditions. In some embodiments, the buprenorphine acetate is substantially pure. In some embodiments, the buprenorphine acetate is substantially more pure. In some embodiments, the buprenorphine acetate is substantially free of impurities. In some embodiments, a method for preparing an acetate salt of buprenorphine comprises the steps of:
(a) contacting buprenorphine free base with a solution comprising acetic acid in a dissolution vessel to form a blend, wherein the blend is at a temperature of about 40 ℃ to about 80 ℃;
(b) optionally filtering the blend of step (a);
(c) adding a reagent to the admixture produced in step (a) or (b) to precipitate the acetate salt of buprenorphine; and
(d) isolating the acetate salt of buprenorphine precipitated in step (c).
In some embodiments, in step (a) of the method, the buprenorphine free base is contacted with from about 2.0 mass equivalents to about 6.0 mass equivalents, or from about 3.0 mass equivalents to about 5.0 mass equivalents, or from about 3.5 mass equivalents to about 4.5 mass equivalents of the acetic acid solution relative to the starting mass of buprenorphine free base.
In some embodiments, the acetic acid solution used in step (a) is an aqueous acetic acid solution. The aqueous acetic acid solution contains at least sufficient concentration of acetic acid to form the acetate salt of all buprenorphine free base starting material in a stoichiometric manner. In some embodiments, the acetic acid in the aqueous solution is present at about 40 wt% to about 70 wt%, or about 45 wt% to about 60 wt%, or about 45 wt% to about 55 wt%, or about 47 wt% to about 55 wt%, or about 49 wt% to about 53 wt%, relative to the weight of the aqueous solution.
In some embodiments, in step (a) of the process, the acetic acid solution supplied to the dissolution vessel is at a temperature of from about 40 ℃ to about 80 ℃, or from about 45 ℃ to about 75 ℃, or from about 50 ℃ to about 70 ℃, or from about 55 ℃ to about 65 ℃. In some embodiments, in step (a) of the process, the acetic acid solution is an aqueous acetic acid solution and is at a temperature of from about 40 ℃ to about 80 ℃, or from about 45 ℃ to about 75 ℃, or from about 50 ℃ to about 70 ℃, or from about 55 ℃ to about 65 ℃ when supplied to the dissolution vessel.
In some embodiments, in step (a) of the method, the admixture is at a temperature of from about 40 ℃ to about 80 ℃, or from about 45 ℃ to about 75 ℃, or from about 50 ℃ to about 70 ℃, or from about 55 ℃ to about 65 ℃ for a period of time such that at least a majority of the buprenorphine free base has dissolved. In some embodiments, the blend is heated to a temperature within a specified temperature range, or in some embodiments, a solution at a temperature within a specified temperature range is added to buprenorphine free base to produce the blend. With respect to the majority of buprenorphine free base that has dissolved, in one embodiment, the majority of buprenorphine free base has dissolved when at least about 30% by weight of the buprenorphine free base has dissolved. In other embodiments, a majority of the buprenorphine free base has dissolved when at least about 50%, at least about 60%, or at least about 75% by weight of the buprenorphine free base has dissolved. The amount corresponding to "most of the buprenorphine free base has dissolved" can be determined from the yield of buprenorphine acetate obtained as follows: if the measured yield of buprenorphine acetate remains relatively constant (within 5%) after addition of an even greater amount of buprenorphine free base, a substantial portion of the buprenorphine free base has dissolved prior to addition of the even greater amount of buprenorphine free base. In some embodiments, the admixture of step (a) is agitated to accelerate dissolution of the buprenorphine free base. Agitation of the blend can be achieved by a variety of techniques including stirring, sonication, or shaking.
In some embodiments, the blend of step (a) may optionally be filtered according to step (b) by using, for example, a filtration device. Filtration can be performed with a filtration device at suitable temperatures, including at temperatures of about 40 ℃ to about 80 ℃, or about 45 ℃ to about 75 ℃, or about 50 ℃ to about 70 ℃, or about 55 ℃ to about 65 ℃. In some embodiments, in step (b), the blend of step (a) added to the filtration device is at a temperature of about 40 ℃ to about 80 ℃ or at a temperature of about 45 ℃ to about 75 ℃. In some embodiments, additional volumes of acetic acid solution are used to flush the dissolution vessel and filtration device. This additional volume of acetic acid solution may be about 0.1 mass equivalents to about 2.0 mass equivalents, or about 0.1 mass equivalents to about 1.1 mass equivalents, or about 0.2 mass equivalents to about 1.5 mass equivalents, or about 0.5 mass equivalents to about 1.1 mass equivalents, or about 0.5 mass equivalents to about 1.0 mass equivalents, or about 0.3 mass equivalents to about 0.5 mass equivalents relative to the starting mass of free base in step (a).
In some embodiments, the additional volume of acetic acid solution is an aqueous acetic acid solution. In some embodiments, the aqueous acetic acid solution may have acetic acid in an amount of about 40 wt% to about 70 wt%, or about 45 wt% to about 60 wt%, or about 45 wt% to about 55 wt%, or about 47 wt% to about 55 wt%, or about 49 wt% to about 53 wt%, relative to the weight of the aqueous solution.
In some embodiments, in step (c) of any of the foregoing methods and variations thereof, the reagent of step (c) is selected from the group consisting of an antisolvent, a seed crystal, and a combination thereof.
In some embodiments, the reagent of step (c) comprises an anti-solvent. Any anti-solvent suitable for precipitation of the starting buprenorphine acetate and achieving a product with the desired characteristics, such as reduced levels of product impurities, may be used. In some embodiments, the anti-solvent comprises water. In some embodiments, about 0.2 mass equivalents to about 8.0 mass equivalents, or about 0.5 mass equivalents to about 4.0 mass equivalents, or about 0.5 mass equivalents to about 2.0 mass equivalents, or about 0.5 mass equivalents to about 1.0 mass equivalents, or about 0.6 mass equivalents to about 0.9 mass equivalents, or about 0.7 mass equivalents to about 0.8 mass equivalents of antisolvent relative to the starting mass of free base in step (a) is added to the blend of step (a) or (b). Generally, the anti-solvent is added at a temperature sufficient to effect precipitation of the buprenorphine acetate. In some embodiments, the anti-solvent is added within about 10 ℃ or within about 5 ℃ of the temperature of the blend of step (a) or step (b) above, particularly at about 45 ℃ to about 75 ℃, or about 50 ℃ to about 70 ℃, or about 50 ℃ to about 65 ℃, or about 55 ℃ to about 65 ℃.
In some embodiments, the anti-solvent is added over a period of time of from about 0.5 hours to about 3.0 hours, or from about 0.5 hours to about 2.5 hours, or from about 1.0 hour to about 2.0 hours.
In some embodiments, the anti-solvent is added in a single portion. In other embodiments, the anti-solvent is added in multiple portions, i.e., in portions. For example, the anti-solvent may be added in step (c) in 2,3, 4,5, 6, 7,8, 9, 10 or more than 10 different portions. The individual amounts of anti-solvent in each part may be the same or different. Part of the anti-solvent may be added during step (c) at well-defined time intervals. For example, in performing step (c), individual portions of anti-solvent may be added about every 0.1 to 4.0 hours, or about every 0.5 hours. Alternatively, when the rate of buprenorphine acetate formation is reduced, individual portions of the anti-solvent may be added from time to time during step (c).
In other embodiments, the anti-solvent is added continuously during step (c). In another embodiment, continuous addition is achieved by slowly dropping the anti-solvent from the addition funnel into the blend. In another embodiment, the continuous addition is achieved by filling a hypodermic syringe equipped with a mechanically driven plunger with the anti-solvent and adding the anti-solvent to the blend via the hypodermic needle. In another embodiment, the continuous addition is achieved by adding the anti-solvent to the blend with a mechanical pump.
Methods for performing portion-wise and continuous addition of anti-solvent are known in the art. For example, U.S. patent nos. 2,191,786, 2,583,420, 3,355,486, 3,749,646, 4,217,787, 6486,692, and 6,994,827, which are hereby incorporated by reference, disclose containers in which an agent is added incrementally to a blend. Incremental addition is known in the art as metering in over a limited period of time, as opposed to adding all of the anti-solvent to the vessel at the same time. The term incremental addition includes the use of continuous flow addition, the use of variable flow addition, the use of individual portion intermittent addition and other related methods. See U.S. patent No. 4,217,287 (column 2, lines 56-62).
In some embodiments, the reagent of step (c) comprises seed crystals. In particular, the seed crystals comprise buprenorphine acetate. The seeds may be added in sufficient quantity to initiate precipitation of the buprenorphine acetate from solution in the blend. In some embodiments, about 0.1 wt% to about 10 wt%, or about 0.1 wt% to about 9 wt%, or about 0.1 wt% to about 8 wt%, or about 0.1 wt% to about 7 wt%, or about 0.1 wt% to about 6 wt%, or about 0.1 wt% to about 5 wt%, or about 0.1 wt% to about 4 wt%, or about 0.1 wt% to about 3 wt%, or about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%, or about 0.2 wt% to about 0.8 wt%, or about 0.3 wt% to about 0.7 wt%, or about 0.4 wt% to about 0.6 wt%, or about 0.2 wt% to about 0.5 wt% of the starting mass of free base in step (a) is added to the blend of step (a) or (b). In some embodiments, about 0.2% to about 9%, or about 0.5% to about 9%, or about 1% to about 5%, or about 2% to about 4% by weight of the seed crystal relative to the starting mass of free base in step (a) is added to the blend of step (a) or (b).
In some embodiments, the seed crystals are added at a suitable temperature to initiate precipitation of the acetate salt. In some embodiments, when seed crystals are added, the blend of step (a) or (b) is at a temperature of from about 40 ℃ to about 80 ℃, or from about 45 ℃ to about 75 ℃, or from about 50 ℃ to about 70 ℃, or from about 50 ℃ to about 65 ℃, or from about 53 ℃ to about 63 ℃, or from about 56 ℃ to about 63 ℃, or from about 58 ℃ to about 62 ℃, or from about 59 ℃ to about 61 ℃.
In some embodiments, in step (c), the agent for precipitating buprenorphine acetate comprises a combination of an anti-solvent and a seed crystal. In some embodiments, the first amount of antisolvent is added before, after, or simultaneously with the addition of the seed crystal. Thereafter a second amount of anti-solvent may be further optionally added. In some embodiments, the first amount of antisolvent is from about 0.2 mass equivalents to about 2.0 mass equivalents, or from about 0.35 mass equivalents to about 0.80 mass equivalents, or from about 0.5 mass equivalents to about 1.0 mass equivalents, or from about 0.6 mass equivalents to about 0.9 mass equivalents, or from about 0.65 mass equivalents to about 0.75 mass equivalents relative to the starting mass of free base in step (a). In some embodiments, when the seed crystals are used in combination with an anti-solvent, about 0.1 wt% to about 10 wt%, or about 0.1 wt% to about 9 wt%, or about 0.1 wt% to about 8 wt%, or about 0.1 wt% to about 7 wt%, or about 0.1 wt% to about 6 wt%, or about 0.1 wt% to about 5 wt%, or about 0.1 wt% to about 4 wt%, or about 0.1 wt% to about 3 wt%, or about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%, or about 0.2 wt% to about 0.8 wt%, or about 0.3 wt% to about 0.7 wt%, or about 0.4 wt% to about 0.6 wt%, or about 0.2 wt% to about 0.5 wt% of the seed crystals are added relative to the starting mass of free base in step (a). In some embodiments, the second optional amount of antisolvent is from about 1.0 mass equivalent to about 8.0 mass equivalents, or from about 0.1 mass equivalents to about 6.5 mass equivalents, or from about 4.0 mass equivalents to about 6.5 mass equivalents, or from about 5.0 mass equivalents to about 6.5 mass equivalents, or from about 5.6 mass equivalents to about 6.1 mass equivalents, or from about 5.75 mass equivalents to about 6.00 mass equivalents, or from about 5.8 mass equivalents to about 6.0 mass equivalents relative to the starting mass of free base in step (a). In some embodiments, the temperature of the blend during the addition of the second optional amount of antisolvent is about the same as the temperature of the blend in step (a). In some embodiments, the temperature of the blend during the addition of the second optional amount of antisolvent is different from the temperature of the blend in step (a). In some embodiments, the temperature of the blend during the addition of the second optional amount of anti-solvent is about the same as the temperature of the blend during the addition of the first amount of anti-solvent. In some embodiments, the temperature of the blend during the addition of the second optional amount of antisolvent is different from the temperature of the blend during the addition of the first amount of antisolvent.
In some embodiments, when precipitation is initiated with seed crystals, the blend may be maintained at the temperature of the blend at the time of seed crystal addition for up to 48 hours, up to 36 hours, up to 24 hours, up to 12 hours, up to 6 hours, up to 5 hours, up to 4 hours, up to 3 hours, up to 2 hours, up to 1 hour, or up to 0.5 hours.
In some embodiments, with respect to any of the foregoing methods, the method may further comprise cooling the blend of step (c) to a temperature of about 30 ℃ or less, about 25 ℃ or less, about 20 ℃ or less, about 15 ℃ or less, or about 10 ℃ or less after the addition of the agent and prior to isolating the acetate salt of buprenorphine in step (d). In some embodiments, the solution is cooled to a temperature of from about 5 ℃ to about 30 ℃, or from about 5 ℃ to about 25 ℃, or from about 5 ℃ to about 20 ℃, or from about 10 ℃ to about 20 ℃.
In some embodiments, with respect to any of the foregoing methods, the method may further comprise adding a co-solvent to the admixture after the precipitation of step (c) but prior to the separation in step (d). In some embodiments, any co-solvent that provides or enhances the desired characteristics of the product (e.g., to reduce product impurity levels) or process (e.g., to reduce foaming) may be used. In some embodiments, the co-solvent is an alcohol, for example selected from methanol, ethanol, isopropanol ("IPA"), and combinations thereof. In some embodiments, the co-solvent is IPA.
In some embodiments, the amount of co-solvent added is from about 0.6 mass equivalents to about 0.8 mass equivalents, or from about 0.75 mass equivalents to about 0.65 mass equivalents, or from about 0.73 mass equivalents to about 0.67 mass equivalents, relative to the starting mass of free base in step (a). In some embodiments, the temperature of the added co-solvent is from about 50 ℃ to about 70 ℃, or from about 52 ℃ to about 68 ℃, or from about 55 ℃ to about 65 ℃.
In some embodiments, after addition of the co-solvent and prior to isolating the acetate salt of buprenorphine in step (d), the method may further comprise cooling the blend to a temperature of about 30 ℃ or less, about 25 ℃ or less, about 20 ℃ or less, about 15 ℃ or less, or about 10 ℃ or less. In some embodiments, the solution is cooled to a temperature of from about 5 ℃ to about 30 ℃, or from about 5 ℃ to about 25 ℃, or from about 5 ℃ to about 20 ℃, or from about 10 ℃ to about 20 ℃. In some embodiments, the cooling rate is from about 1 ℃/h to about 20 ℃/h, or from about 4 ℃/h to about 15 ℃/h, or from about 5 ℃/h to about 12 ℃/h, or from about 6 ℃/h to about 10 ℃/h.
After precipitation of the buprenorphine acetate in step (c), the method further comprises a step (d) of isolating the buprenorphine acetate. In some embodiments, the separation in step (d) is achieved by filtration, centrifugation, wet milling or decantation.
In some embodiments, the method further comprises slurrying the buprenorphine acetate obtained from step (d) with a slurrying solution. In some embodiments, the slurrying solution comprises an alcohol, such as IPA, or water and an alcohol, such as water and IPA. The slurry may be filtered to provide a formulation of buprenorphine acetate.
As discussed above, the buprenorphine acetate and polymorphs thereof prepared by any of the methods described above are substantially free of impurities, and thus in some embodiments produce substantially pure buprenorphine acetate. Some of the impurities produced during buprenorphine synthesis have chemical properties similar to buprenorphine, which tend to make purification of the final product difficult. As noted above, it has been found that buprenorphine acetate, and in particular buprenorphine acetate prepared by the methods disclosed herein, has lower impurity levels, and in some embodiments is substantially free of impurities. Without being bound by theory, it is believed that the reduction of impurities occurs during precipitation of crystalline buprenorphine acetate; it is believed that the undesired impurities remain in solution in the admixture of step (c) after isolation of the buprenorphine acetate. Thus, in another aspect, the present disclosure provides buprenorphine acetate, and in particular a compound of formula (1b), prepared by any of the methods described herein, each having an advantageously improved impurity profile.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (10):
Figure BDA0001463758400000471
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (11):
Figure BDA0001463758400000481
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by a compound of formula (12):
Figure BDA0001463758400000482
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (13):
Figure BDA0001463758400000491
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (14):
Figure BDA0001463758400000492
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (15):
Figure BDA0001463758400000501
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (16):
Figure BDA0001463758400000502
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (17):
Figure BDA0001463758400000511
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (18):
Figure BDA0001463758400000512
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) comprise about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (19):
Figure BDA0001463758400000521
or a salt thereof.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) are substantially free of impurities. In some embodiments, the total amount of impurities (including the combined level of impurities for compounds of formulas (10), (11), (12), (13), (14), and (15)) is about 0.70 wt.% or less, about 0.65 wt.% or less, about 0.60 wt.% or less, about 0.55 wt.% or less, about 0.50 wt.% or less, about 0.45 wt.% or less, about 0.40 wt.% or less, about 0.35 wt.% or less, about 0.30 wt.% or less, about 0.25 wt.% or less, about 0.20 wt.% or less, about 0.15 wt.% or less, or about 0.10 wt.% or less.
In some embodiments, buprenorphine acetate formulations of the present disclosure (including anhydrates, solvates, hydrates, and crystalline forms thereof) are substantially free of impurities. In some embodiments, the total amount of impurities (including the combined level of impurities for compounds of formulas (10), (11), (12), (13), (14), (15), (16), (17), (18), and (19)) is about 0.70 wt.% or less, about 0.65 wt.% or less, about 0.60 wt.% or less, about 0.55 wt.% or less, about 0.50 wt.% or less, about 0.45 wt.% or less, about 0.40 wt.% or less, about 0.35 wt.% or less, about 0.30 wt.% or less, about 0.25 wt.% or less, about 0.20 wt.% or less, about 0.15 wt.% or less, or about 0.10 wt.% or less.
4.4 buprenorphine free base, buprenorphine salts and methods of making the same
As discussed above, buprenorphine acetate and solvates, hydrates, anhydrates and crystalline forms thereof allow for the isolation of impurities present in current buprenorphine formulations, and thus provide synthetic intermediates for the preparation of buprenorphine of increased purity, including its free base and other salt forms. By using the methods of the present disclosure, buprenorphine, including the free base, salt forms, solvates, hydrates, anhydrates and crystalline forms thereof, can be prepared substantially free of impurities.
Accordingly, in another aspect, the present disclosure provides a method for preparing buprenorphine free base, the method comprising treating an acetate salt of buprenorphine under conditions sufficient to remove the acetate counterion, thereby providing buprenorphine free base (and acetic acid). In some embodiments, the treating step removes acetate counterions sufficiently to produce substantially pure buprenorphine free base. In some embodiments, the amount of acetate salt remaining in the buprenorphine free base formulation is less than about 0.10%, less than about 0.09%, less than about 0.08%, less than about 0.07%, less than about 0.06%, or less than about 0.05% by weight.
A first method for the preparation of buprenorphine free base from an acetate salt of buprenorphine, for example from buprenorphine acetate tetrahydrate, comprises the steps of:
(a) contacting an acetate salt of buprenorphine with the solution and a basic material to form a blend;
(b) agitating the admixture of step (a) at a temperature of about 20 ℃ to about 90 ℃ to provide buprenorphine free base;
(c) isolating the buprenorphine free base of step (b); and
(d) optionally repeating steps (a) to (c) one or more times.
In some embodiments of this first method for preparing buprenorphine free base from an acetate salt of buprenorphine, in step (a), the acetate salt of buprenorphine is contacted with at least about the same mass (i.e., about 1 mass equivalent) of the solution relative to the starting mass of the acetate salt in step (a). In some embodiments, in step (a), the acetate salt of buprenorphine is contacted with from about 1.0 mass equivalents to about 6.0 mass equivalents, or from about 2.0 mass equivalents to about 5.0 mass equivalents, or from about 2.0 mass equivalents to about 4.0 mass equivalents, or from about 3.0 mass equivalents to about 4.0 mass equivalents of the solution relative to the starting mass of the acetate salt in step (a). The acetate salt of buprenorphine is at least partially dissolved in the solution; however, buprenorphine free base is relatively insoluble therein and can precipitate. In some embodiments, the solution of step (a) comprises water and an alcohol. In some embodiments, the water and alcohol solution comprises from about 30% to about 70% alcohol by weight in water, or from about 40% to about 60% alcohol by weight in water, or from about 50% to about 60% alcohol by weight in water. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, IPA, and combinations thereof. In some embodiments, the alcohol is IPA. In some embodiments, the water and alcohol solution comprises from about 30% to about 70% IPA by weight in water, or from about 40% to about 60% IPA by weight in water, or from about 50% to about 60% IPA by weight in water.
In some embodiments of this first method for preparing buprenorphine free base from an acetate salt of buprenorphine, the basic material used in step (a) may be any base suitable for use in preparing buprenorphine free base. In some embodiments, the basic material is selected from the group consisting of hydroxides, carbonates, alkoxides, hydrides, phosphates, borates (such as borax), oxides (such as CaO), cyanides (such as KCN), silicates (such as sodium metasilicate), amines (such as triethylamine, pyridine, or 4-dimethylaminopyridine), and the like, and combinations thereof. In some embodiments, the alkaline material comprises a hydroxide. In some embodiments, the basic material comprises ammonium hydroxide. In some embodiments, the alkaline material is an aqueous ammonium hydroxide solution.
In some embodiments, the acetate salt of buprenorphine is contacted with from about 0.5 molar equivalents to about 20 molar equivalents, or from about 1 molar equivalent to about 10 molar equivalents of the basic material relative to the starting molar number of the acetate salt of buprenorphine in step (a).
In some embodiments, agitating the blend in step (b) may be performed by any suitable method, such as by shaking, stirring, or sonicating the blend. In some embodiments, in step (b), the blend is agitated for a time sufficient to remove the acetate counterions. In some embodiments, the admixture of step (a) is agitated in step (b) for about 1h to about 36h, or about 1h to about 24h, or about 2h to about 20h, or about 2h to about 8h, or about 3h to about 7h, or about 4 to about 6 h. In some embodiments, in step (b), the blend is agitated at a temperature of from about 25 ℃ to about 90 ℃, or from about 25 ℃ to about 60 ℃, or from about 30 ℃ to about 45 ℃.
In this first method for the preparation of buprenorphine free base from an acetate salt of buprenorphine, the free base formed in step (b) is isolated in step (c), for example by precipitation. Any suitable method for isolating the buprenorphine free base may be used. In some embodiments, the separation in step (c) is achieved by filtration or by centrifugation to obtain a separated precipitate.
In some embodiments, the method for preparing buprenorphine free base from an acetate salt of buprenorphine optionally further comprises step (d), i.e., repeating steps (a) to (c) one or more times. In some embodiments of step (d), steps (a) to (c) are repeated once, twice, three times, or at least three times.
In some embodiments, the free base isolated in step (c) may be subsequently processed. Thus, in some embodiments, the method for preparing buprenorphine free base from an acetate salt of buprenorphine may further comprise the step of slurrying the isolated solid product of step (c) with a slurrying solution. In some embodiments, the slurrying solution comprises a water and alcohol mixture. In some embodiments, the slurrying solution comprises IPA in water, wherein the alcohol is present at about 5 wt% to about 40 wt%, or about 5 wt% to about 30 wt%, or about 10 wt% to about 30 wt%. The free base may then be separated from the slurry, such as by filtration or by centrifugation. In some embodiments, the pulping temperature is from about 5 ℃ to about 40 ℃, or from about 10 ℃ to about 35 ℃, or from about 15 ℃ to about 35 ℃.
In some embodiments of this first method, the acetic acid in the final buprenorphine free base formulation is present at less than about 0.7%, less than about 0.5%, less than about 0.3%, less than about 0.2%, or less than about 0.1% by weight after the first method is performed.
In another aspect, the present disclosure provides buprenorphine free base prepared by the first method or by any of the variations thereof described above. In some embodiments, the buprenorphine free base prepared by the first method is substantially free of impurities.
In some embodiments, the buprenorphine free base prepared by the first method comprises about 0.10% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, or about 0.05% by weight or less of an impurity represented by a compound of formula (10):
Figure BDA0001463758400000561
in some embodiments, the buprenorphine free base prepared by the first method comprises about 0.10% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, or about 0.05% by weight or less of an impurity represented by a compound of formula (11):
Figure BDA0001463758400000562
in some embodiments, the buprenorphine free base prepared by the first method comprises about 0.10% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, or about 0.05% by weight or less of an impurity represented by a compound of formula (12):
Figure BDA0001463758400000571
in some embodiments, the buprenorphine free base prepared by the first method comprises about 0.10% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, or about 0.05% by weight or less of an impurity represented by a compound of formula (13):
Figure BDA0001463758400000572
in some embodiments, the buprenorphine free base prepared by the first method comprises about 0.10% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, or about 0.05% by weight or less of an impurity represented by a compound of formula (14):
Figure BDA0001463758400000573
Figure BDA0001463758400000581
in some embodiments, the buprenorphine free base prepared by the first method comprises about 0.10% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, or about 0.05% by weight or less of an impurity represented by a compound of formula (15):
Figure BDA0001463758400000582
in some embodiments, the combined level of impurities for the compounds of formulae (10), (11), (12), (13), (14), and (15) with respect to the free base formulation of buprenorphine prepared by the first method is about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
In some embodiments, the combined level of the impurities of the compounds of formulae (10), (11), (12), (13), (14), and (15), and any other impurity or impurities not specifically identified herein, with respect to the free base formulation of buprenorphine prepared by the first method, is about 0.75 wt% or less, about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
Alternatively, the buprenorphine free base may be prepared from the acetate salt of buprenorphine by removing the acetate counterion using methods such as by heating, evaporation at about atmospheric pressure, evaporation at sub-atmospheric pressure, or any combination thereof.
Alternatively, a second method for preparing buprenorphine free base from an acetate salt of buprenorphine, for example, from buprenorphine acetate tetrahydrate, comprises treating the acetate salt of buprenorphine at a pressure, temperature and for a period of time sufficient to remove acetic acid and water, thereby providing the buprenorphine free base. In some embodiments, the treatment is at a temperature of at least about 30 ℃ for a period of time sufficient to remove acetic acid and water. In some embodiments, such treatment lasts at least 1 h.
In some embodiments of this second method, the acetate salt of buprenorphine is treated at a sub-atmospheric pressure, e.g., at a pressure of from about 50 torr to about 250 torr, or from about 75 torr to about 225 torr, or from about 100 torr to about 200 torr, or from about 125 torr to about 175 torr. In some embodiments, such treatment is performed at about 150 torr.
In some embodiments of this second method, the acetate salt of buprenorphine is treated at about atmospheric pressure, e.g., at a pressure of from about 620 torr to about 780 torr, or from about 670 torr to about 780 torr, or from about 700 torr to about 780 torr, or from about 740 torr to about 780 torr, or from about 750 torr to about 770 torr, or from about 755 torr to about 765 torr. In some embodiments, such treatment is performed at atmospheric pressure of about 760 torr.
In some embodiments of this second method for preparing buprenorphine free base from an acetate salt of buprenorphine, the acetate salt of buprenorphine is treated at a temperature of at least about 45 ℃, at least about 50 ℃, or at least about 65 ℃. In some embodiments of this second method for preparing buprenorphine free base from an acetate salt of buprenorphine, the treatment temperature is from about 50 ℃ to about 110 ℃, or from about 50 ℃ to about 105 ℃, or from about 60 ℃ to about 100 ℃, or from about 65 ℃ to about 100 ℃.
In some embodiments of this second method, the heating at the treatment temperature is for at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 9 hours, at least about 10 hours, at least about 12 hours, or for a time sufficient to form substantially pure buprenorphine free base.
In some embodiments, this second method for preparing buprenorphine free base from an acetate salt of buprenorphine further comprises slurrying the free base with the slurrying solution and filtering the solid free base therefrom. In some embodiments, the slurrying solution comprises water and an alcohol, as disclosed above with respect to the first method.
In some embodiments of this second method, the acetic acid in the final buprenorphine free base formulation is present at less than about 0.7%, less than about 0.5%, less than about 0.3%, less than about 0.2%, or less than about 0.1% by weight.
In another aspect, the present disclosure provides buprenorphine free base prepared by the second method or by any of the variations thereof described above. In some embodiments, the buprenorphine free base formulation prepared by the second method is substantially free of impurities.
In some embodiments, the buprenorphine free base prepared by the second method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of impurities represented by the compound of formula (10).
In some embodiments, the buprenorphine free base prepared by the second method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (11).
In some embodiments, the buprenorphine free base prepared by the second method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (12).
In some embodiments, the buprenorphine free base prepared by the second method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (13).
In some embodiments, the buprenorphine free base prepared by the second method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (14).
In some embodiments, the buprenorphine free base prepared by the second method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (15).
In some embodiments, the combined level of impurities for the compounds of formulae (10), (11), (12), (13), (14), and (15) with respect to the buprenorphine free base prepared by the second method is about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
In some embodiments, the combined level of impurities of the compounds of formulae (10), (11), (12), (13), (14), and (15), and any other impurity or impurities not specifically identified herein, with respect to the buprenorphine free base prepared by the second method is about 0.75 wt% or less, about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
A third method for preparing buprenorphine free base from the acetate salt of buprenorphine, for example from buprenorphine acetate tetrahydrate, comprises the steps of:
(a) dissolving an acetate salt of buprenorphine in a solution to form a blend;
(b) optionally filtering the blend of step (a);
(c) adding a basic material to the blend of step (a) or (b) to form a second blend;
(d) adding an anti-solvent to the second admixture produced in step (c) to form a precipitate of buprenorphine free base; and
(e) isolating the precipitate of step (d).
In some embodiments of this third method for preparing buprenorphine free base from an acetate salt of buprenorphine, the admixture of step (a) comprises an organic solvent. In some embodiments, the organic solvent comprises an alcohol. In some embodiments, the organic solvent comprises an alcohol selected from the group consisting of methanol, ethanol, and isopropanol. In some embodiments, the alcohol is selected from methanol, ethanol, and isopropanol. In some embodiments, the alcohol is IPA. In some embodiments, the acetate salt of buprenorphine is contacted with at least about 3.0 mass equivalents of the solution relative to the starting mass of the acetate salt of buprenorphine in step (a).
In some embodiments of this third method, in step (a), the blend is at a temperature of about 20 ℃ to about 90 ℃. In some embodiments, in step (a), the blend is at a temperature of at least about 20 ℃, at least about 40 ℃, at least about 50 ℃, at least about 55 ℃, or at least about 60 ℃. The blend can be brought to a temperature within the specified temperature range by a variety of methods, such as by heating the blend or by using a solution at a temperature within the specified temperature range. In some embodiments, the blend is mixed until substantially all of the buprenorphine acetate is dissolved in the solution.
In one embodiment of this third method, substantially all of the buprenorphine acetate salt dissolves when at least about 80.0%, at least about 85.0%, at least about 90.0%, at least about 95.0%, at least about 98.0%, at least about 99.0%, at least about 99.5%, at least about 99.8%, or at least about 99.9% by weight of the buprenorphine acetate salt dissolves.
In some embodiments of this third method, the blend of step (a) is filtered in step (b). Filtration step (b) removes undissolved solids.
In some embodiments of this third method, in step (c), about 1.0 molar equivalents to about 20.0 molar equivalents, or about 1.0 molar equivalents to about 5.0 molar equivalents, or about 1.0 molar equivalents to about 2.0 molar equivalents, or about 1.0 molar equivalents to about 1.2 molar equivalents of the basic material relative to the starting moles of the acetate salt of buprenorphine in step (a) is added to the blend produced in step (a) or (b).
In some embodiments of this third method, the basic material used in step (c) can be any base suitable for use in the preparation of buprenorphine free base. In some embodiments, the basic material is selected from the group consisting of hydroxides, carbonates, alkoxides, hydrides, phosphates, borates (such as borax), oxides (such as CaO), cyanides (such as KCN), silicates (such as sodium metasilicate), amines (such as triethylamine, pyridine, or 4-dimethylaminopyridine), and the like, and combinations thereof. In some embodiments, the alkaline material comprises a hydroxide. In some embodiments, the basic material comprises ammonium hydroxide. In some embodiments, the alkaline material is an aqueous ammonium hydroxide solution.
In some embodiments of this third method, in step (d), at least about 3.0 mass equivalents of an anti-solvent relative to the starting mass of the acetate salt in step (a) is added to the second admixture produced in step (c) so as to provide a precipitate of buprenorphine free base.
In some embodiments of the third method, the anti-solvent consists essentially of water. In some embodiments, the anti-solvent comprises a mixture of water and an alcohol. In some embodiments, in the mixture of water and alcohol, the alcohol comprises IPA. In some embodiments, in the mixture of water and alcohol, the alcohol is IPA. In some embodiments, the water and alcohol mixture is from about 95: 5 to about 50: 50 water to alcohol by volume, or from about 90: 10 to about 60: 40 water to alcohol by volume, or from about 85: 15 to about 70: 30 water to alcohol by volume. In some embodiments, the water and alcohol mixture is about 80: 20 water to alcohol by volume. In some embodiments, the water and alcohol mixture is from about 95: 5 to about 50: 50 water to IPA by volume, or from about 90: 10 to about 60: 40 water to IPA by volume, or from about 85: 15 to about 70: 30 water to IPA by volume. In some embodiments, the water and alcohol mixture is about 80: 20 water to IPA by volume.
In some embodiments of the third method, the minimum time for the formation of a precipitate of buprenorphine free base in step (d) is about 0.1 h. In some embodiments, the time for forming a precipitate of buprenorphine free base is from about 0.1h to about 10.0h, or from about 0.1h to about 6.0h, or from about 0.2h to about 5.0h, or from about 0.1h to about 3.0h, or from about 0.3h to about 3.0h, or from about 0.5h to about 3.0 h.
Optionally, in some embodiments of the third method, seed crystals are added in step (d). In particular, the seed crystals comprise buprenorphine free base. The seed crystals may be added in sufficient quantity to initiate precipitation or assisted precipitation of the buprenorphine free base from the second admixture. In some embodiments, about 0.1 wt% to about 10 wt%, or about 0.1 wt% to about 9 wt%, or about 0.1 wt% to about 8 wt%, or about 0.1 wt% to about 7 wt%, or about 0.1 wt% to about 6 wt%, or about 0.1 wt% to about 5 wt%, or about 0.1 wt% to about 4 wt%, or about 0.1 wt% to about 3 wt%, or about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%, or about 0.2 wt% to about 0.8 wt%, or about 0.3 wt% to about 0.7 wt%, or about 0.4 wt% to about 0.6 wt%, or about 0.2 wt% to about 0.5 wt% of the starting mass of the acetate salt in step (a) is added to the second blend of step (d). In some embodiments, about 0.2% to about 9%, or about 0.5% to about 9%, or about 1% to about 5%, or about 2% to about 4% by weight of the seed crystal relative to the starting mass of acetate in step (a) is added to the second blend of step (d).
In some embodiments, the seed crystals are added at a suitable temperature to initiate precipitation of the buprenorphine free base. In some embodiments, when seed crystals are added, the second blend of step (d) is at a temperature of from about 40 ℃ to about 80 ℃, or from about 45 ℃ to about 75 ℃, or from about 50 ℃ to about 70 ℃, or from about 50 ℃ to about 65 ℃.
In some embodiments of this third method, the buprenorphine free base prepared in step (d) is isolated in step (e). In some embodiments, the separation is achieved by filtration. In some embodiments, the separation in step (e) is performed at a temperature of at least about 70 ℃, at least about 65 ℃, at least about 60 ℃, at least about 50 ℃, or at least about 40 ℃.
In some embodiments, this third method for preparing buprenorphine free base further comprises the step of slurrying the free base obtained from step (e) with a slurrying solution. In some embodiments, the slurrying solution comprises water or a mixture of water and alcohol. In some embodiments, the alcohol comprises IPA. After forming this slurry, the free base can be separated from the slurry, for example, by filtration or by centrifugation.
In some embodiments of this third method, the acetic acid in the final buprenorphine free base formulation is present at less than about 0.7%, less than about 0.5%, less than about 0.3%, less than about 0.2%, or less than about 0.1% by weight.
In another aspect, the present disclosure provides buprenorphine free base prepared by the third method or by any of the variations thereof described above. In some embodiments, the buprenorphine free base formulation prepared by the third method is substantially free of impurities.
In some embodiments, the buprenorphine free base prepared by the third method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of impurities represented by compound of formula (10).
In some embodiments, the buprenorphine free base prepared by the third method comprises about 0.10% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, or about 0.05% by weight or less of an impurity represented by the compound of formula (11).
In some embodiments, the buprenorphine free base prepared by the third method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (12).
In some embodiments, the buprenorphine free base prepared by the third method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (13).
In some embodiments, the buprenorphine free base prepared by the third method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (14).
In some embodiments, the buprenorphine free base prepared by the third method comprises about 0.10% by weight or less, about 0.09% by weight or less, about 0.08% by weight or less, about 0.07% by weight or less, about 0.06% by weight or less, or about 0.05% by weight or less of an impurity represented by the compound of formula (15).
In some embodiments, the combined level of impurities for the compounds of formulae (10), (11), (12), (13), (14), and (15) with respect to the buprenorphine free base prepared by the third method is about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
In some embodiments, the combined level of impurities of the compounds of formulae (10), (11), (12), (13), (14), and (15), and any other impurity or impurities not specifically identified herein, with respect to the buprenorphine free base prepared by the third method is about 0.75 wt% or less, about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
A fourth method for preparing buprenorphine free base from an acetate salt of buprenorphine, for example, from buprenorphine acetate tetrahydrate, comprises:
(a) heating a blend of an acetate salt of buprenorphine and an aqueous solution to provide precipitated buprenorphine free base; and
(b) filtering the blend of step (a) to provide buprenorphine free base from the precipitate.
In some embodiments of this fourth method for preparing buprenorphine free base from an acetate salt of buprenorphine, the aqueous solution consists essentially of water. In some embodiments of this fourth method for preparing buprenorphine free base from an acetate salt of buprenorphine, the aqueous solution comprises a mixture of water and an alcohol. In some embodiments, in the mixture of water and alcohol, the alcohol comprises IPA. In some embodiments, in the mixture of water and alcohol, the alcohol is IPA. In some embodiments, the water and alcohol mixture is from about 95: 5 to about 50: 50 water to alcohol by volume, or from about 90: 10 to about 60: 40 water to alcohol by volume, or from about 85: 15 to about 70: 30 water to alcohol by volume. In some embodiments, the water and alcohol mixture is about 80: 20 water to alcohol by volume. In some embodiments, the water and alcohol mixture is from about 95: 5 to about 50: 50 water to IPA by volume, or from about 90: 10 to about 60: 40 water to IPA by volume, or from about 85: 15 to about 70: 30 water to IPA by volume. In some embodiments, the water and alcohol mixture is about 80: 20 water to IPA by volume.
In some embodiments of this fourth method for preparing buprenorphine free base, the blend is heated to a temperature of from about 70 ℃ to about 90 ℃.
In some embodiments, the fourth method further comprises washing the solid filtered product of step (b) with a second aqueous solution one or more times. The second aqueous solution may be water or a mixture of water and alcohol as above.
In some embodiments, the fourth method further comprises the step of drying the solid filtered solid product of step (b).
In some embodiments of this fourth method, the acetic acid in the final buprenorphine free base formulation is present at less than about 0.7%, less than about 0.5%, less than about 0.3%, less than about 0.2%, or less than about 0.1% by weight.
In another aspect, the present disclosure provides buprenorphine free base prepared by the fourth method or by any of the variations thereof described above. In some embodiments, the buprenorphine free base prepared by the fourth method is substantially free of impurities.
In some embodiments, the buprenorphine free base prepared by the fourth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of impurities represented by compound of formula (10).
In some embodiments, the buprenorphine free base prepared by the fourth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (11).
In some embodiments, the buprenorphine free base prepared by the fourth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (12).
In some embodiments, the buprenorphine free base prepared by the fourth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (13).
In some embodiments, the buprenorphine free base prepared by the fourth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (14).
In some embodiments, the buprenorphine free base prepared by the fourth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (15).
In some embodiments, the combined level of impurities for the compounds of formulae (10), (11), (12), (13), (14), and (15) with respect to the buprenorphine free base prepared by the fourth method is about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
In some embodiments, the combined level of impurities of the compounds of formulae (10), (11), (12), (13), (14), and (15), and any other impurity or impurities not specifically identified herein, with respect to the buprenorphine free base prepared by the fourth method is about 0.75 wt% or less, about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
A fifth method for preparing buprenorphine free base from an acetate salt of buprenorphine, for example, from buprenorphine acetate tetrahydrate, comprises:
(a) mixing an acetate salt of buprenorphine in a solvent to form a blend;
(b) refluxing the blend at reflux temperature and removing acetate salt in the form of acetic acid in the vapor phase;
(c) cooling the blend to provide precipitated buprenorphine free base; and
(d) the buprenorphine free base is isolated.
In some embodiments of this fifth method for preparing buprenorphine free base from an acetate salt of buprenorphine, the isolating of step (d) comprises filtering the precipitated buprenorphine free base of step (c).
In some embodiments of this fifth method, the solvent comprises an organic solvent. In some embodiments, the organic solvent may be selected from the group consisting of hexane, heptane, IPA, methanol, ethanol, n-propanol, n-butanol, isobutanol, tertiary butanol, acetonitrile, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexane, toluene, tetrahydrofuran, and any mixture of two or more thereof.
In any of the above embodiments of the fifth process, the removal of acetic acid may be performed using a condenser in combination with a distillation head or a Dean-Stark trap.
In some embodiments of this fifth method, the acetic acid in the final buprenorphine free base formulation is present at less than about 0.7%, less than about 0.5%, less than about 0.3%, less than about 0.2%, or less than about 0.1% by weight.
In another aspect, the present disclosure provides buprenorphine free base prepared by the fifth method or by any of the variations thereof described above. In some embodiments, the buprenorphine free base prepared by the fifth method is substantially free of impurities.
In some embodiments, the buprenorphine free base prepared by the fifth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of impurities represented by compound of formula (10).
In some embodiments, the buprenorphine free base prepared by the fifth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (11).
In some embodiments, the buprenorphine free base prepared by the fifth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (12).
In some embodiments, the buprenorphine free base prepared by the fifth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (13).
In some embodiments, the buprenorphine free base prepared by the fifth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (14).
In some embodiments, the buprenorphine free base prepared by the fifth method comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by the compound of formula (15).
In some embodiments, the combined level of impurities for the compounds of formulae (10), (11), (12), (13), (14), and (15) with respect to the buprenorphine free base prepared by the fifth method is about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
In some embodiments, the combined level of impurities of the compounds of formulae (10), (11), (12), (13), (14), and (15), and any other impurity or impurities not specifically identified herein, with respect to the buprenorphine free base prepared by the fifth method, is about 0.75 wt% or less, about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
In another aspect, the present disclosure also provides other buprenorphine salts prepared from the free base, wherein the free base is prepared from an acetate salt of buprenorphine as described herein. Thus, in some embodiments, the buprenorphine salt may be represented by formula (1c),
Figure BDA0001463758400000711
or a solvate thereof;
wherein Xn-Is an anion and n is 1, 2 or 3. In certain embodiments, Xn-Is selected from F-、Cl-、Br-、I-Valeric acid radical, acetic acid radical, pyromellitic acid radical, salicylic acid radical, barbituric acid radical, succinic acid radical, tartaric acid radical, maleic acid radical, fumaric acid radical, citric acid radical, methanesulfonic acid radical, toluenesulfonic acid radical, trifluoroacetic acid radical, oxalic acid radical, perchloric acid radical, NO3 -、HSO4 -、SO4 2-、H2PO4 -、HPO4 2-、PO4 3-、[(NH4)HPO4]-、[(NH4)2PO4]-And HCOO-The anion of (4). In another embodiment, Xn-Is Cl-。
(1c) Salts can be prepared by adding the acid H to the buprenorphine free base+ nXn-To obtain the final product.
In some embodiments, acid H+ nXn-Selected from HCl and H2SO4、H3PO4And HCOOH. In another embodiment, the acid H+ nXn-Is HCl.
In some embodiments, the amount of acid added to the buprenorphine free base is from about 0.5 molar equivalents to about 10 molar equivalents based on the total molar equivalents of free base present in the composition. In some embodiments, the amount of acid is from about 1 molar equivalent to about 6 molar equivalents. In some embodiments, the amount of acid is from about 2 molar equivalents to about 3 molar equivalents. In some embodiments, the amount of acid is from about 2.2 molar equivalents to about 2.6 molar equivalents.
In some embodiments, the salt of formula (1c) may be an anhydrate, a solvate, or a hydrate. In some embodiments, the salt of formula (1c) is an anhydrate. In some embodiments, the salt of formula (1c) is a hydrate and the hydrate is a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, or hexahydrate. In some embodiments, the hydrate is a tetrahydrate.
In some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (10):
Figure BDA0001463758400000731
in some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (11):
Figure BDA0001463758400000732
in some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (12):
Figure BDA0001463758400000741
in some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (13):
Figure BDA0001463758400000742
in some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (14):
Figure BDA0001463758400000743
Figure BDA0001463758400000751
in some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (15):
Figure BDA0001463758400000752
in some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (16):
Figure BDA0001463758400000753
in some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (17):
Figure BDA0001463758400000761
in some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (18):
Figure BDA0001463758400000762
in some embodiments, the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10% or less, about 0.09% or less, about 0.08% or less, about 0.07% or less, about 0.06% or less, or about 0.05% or less by weight of an impurity represented by a compound of formula (19):
Figure BDA0001463758400000763
Figure BDA0001463758400000771
in some embodiments, the salt prepared from the buprenorphine free base prepared by any of the methods above comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (10):
Figure BDA0001463758400000772
or a salt thereof.
In some embodiments, the salt prepared from the buprenorphine free base prepared by any of the foregoing methods comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (11):
Figure BDA0001463758400000773
or a salt thereof.
In some embodiments, the salt prepared from the buprenorphine free base prepared by any of the methods above comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by a compound of formula (12):
Figure BDA0001463758400000781
or a salt thereof.
In some embodiments, the salt prepared from the buprenorphine free base prepared by any of the methods above comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (13):
Figure BDA0001463758400000782
or a salt thereof.
In some embodiments, the salt prepared from the buprenorphine free base prepared by any of the methods above comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (14):
Figure BDA0001463758400000791
or a salt thereof.
In some embodiments, the salt prepared from the buprenorphine free base prepared by any of the methods above comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by a compound of formula (15):
Figure BDA0001463758400000792
or a salt thereof.
In some embodiments, the salt prepared from the buprenorphine free base prepared by any of the methods above comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (16):
Figure BDA0001463758400000801
or a salt thereof.
In some embodiments, the salt prepared from the buprenorphine free base prepared by any of the methods above comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by a compound of formula (17):
Figure BDA0001463758400000802
or a salt thereof.
In some embodiments, the salt prepared from the buprenorphine free base prepared by any of the methods above comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (18):
Figure BDA0001463758400000811
or a salt thereof.
In some embodiments, the salt prepared from the buprenorphine free base prepared by any of the methods above comprises about 0.10 wt% or less, about 0.09 wt% or less, about 0.08 wt% or less, about 0.07 wt% or less, about 0.06 wt% or less, or about 0.05 wt% or less of an impurity represented by the compound of formula (19):
Figure BDA0001463758400000812
or a salt thereof.
In some embodiments, the buprenorphine free base, and salts and pharmaceutical compositions prepared therefrom, prepared by any of the foregoing methods are substantially free of impurities. In some embodiments, the combined level of impurities for the compounds of formulae (10), (11), (12), (13), (14), (15), (16), (17), (18), and (19) that may be present with respect to buprenorphine free base and salts prepared therefrom by any of the foregoing methods is about 0.70 wt% or less, about 0.65 wt% or less, about 0.60 wt% or less, about 0.55 wt% or less, about 0.50 wt% or less, about 0.45 wt% or less, about 0.40 wt% or less, about 0.35 wt% or less, about 0.30 wt% or less, about 0.25 wt% or less, or about 0.20 wt% or less.
In some embodiments, the total amount of impurities, including the combined levels of impurities for the compounds of formulae (10), (11), (12), (13), (14), (15), (16), (17), (18), and (19), in relation to the buprenorphine free base and salts prepared therefrom prepared by any of the foregoing methods, is about 0.70 wt.% or less, about 0.65 wt.% or less, about 0.60 wt.% or less, about 0.55 wt.% or less, about 0.50 wt.% or less, about 0.45 wt.% or less, about 0.40 wt.% or less, about 0.35 wt.% or less, about 0.30 wt.% or less, about 0.25 wt.% or less, about 0.20 wt.% or less, about 0.15 wt.% or less, or about 0.10 wt.% or less.
In some embodiments, the total amount of impurities, including the combined levels of impurities of the compounds of formulae (10), (11), (12), (13), (14), (15), (16), (17), (18), and (19) and any other impurity or impurities not specifically identified herein, that may be present, is about 0.75 wt.% or less, about 0.70 wt.% or less, about 0.65 wt.% or less, about 0.60 wt.% or less, about 0.55 wt.% or less, about 0.50 wt.% or less, about 0.45 wt.% or less, about 0.40 wt.% or less, about 0.35 wt.% or less, about 0.30 wt.% or less, about 0.25 wt.%, about 0.20 wt.% or less, about 0.15 wt.% or less, or about 0.10 wt.% or less with respect to the free base of buprenorphine prepared by any of the foregoing methods.
In some embodiments, with respect to buprenorphine free base prepared by any of the methods above and salts and pharmaceutical compositions prepared therefrom, the amount of a particular impurity of a compound of formulae (10) to (19), particularly compounds of formulae (10) to (15), is at or below a critical level (or threshold) specified by the united states pharmacopeia ("USP"), FDA, EMA, or ICH monograph/guideline for buprenorphine. In some embodiments, the buprenorphine free base and salts and pharmaceutical compositions prepared therefrom prepared by any of the methods above have levels at or below the threshold or critical values (in weight%) provided in table 2 for all impurities set forth in table 2 below.
TABLE 2
Figure BDA0001463758400000831
1ND is not tested, NT is not tested2Not exceeding NMT ═
In some embodiments, the buprenorphine free base and salts and pharmaceutical compositions prepared therefrom prepared by any of the methods above are characterized by a measured impurity profile for all of the impurities set forth in table 2 above that is at or below the level of the measured impurity profile provided in table 2.
In some embodiments, the buprenorphine free base prepared by any of the foregoing methods is converted to a pharmaceutically acceptable salt thereof by reacting the buprenorphine free base with an appropriate acid as directed in the present disclosure, or by any of a variety of known methods in view of the present disclosure. In one embodiment, the buprenorphine free base prepared by any of the foregoing methods is converted to buprenorphine hydrochloride by reacting the buprenorphine free base with HCl. In one embodiment, the buprenorphine free base prepared by any of the methods above is converted to the levulinic acid salt of buprenorphine by reacting the buprenorphine free base with levulinic acid.
4.5 pharmaceutical compositions
In another aspect, the present disclosure also provides pharmaceutical compositions of buprenorphine compounds including the corresponding salts, solvates, hydrates, and crystalline forms, and in particular pharmaceutically acceptable salts of buprenorphine, prepared according to the methods described herein.
Thus, in some embodiments, the pharmaceutical compositions of the present disclosure comprise an acetate salt of buprenorphine. In some embodiments, the pharmaceutical compositions of the present disclosure comprise a hydrochloride salt of buprenorphine. In some embodiments, the pharmaceutical compositions of the present disclosure comprise a levulinate salt of buprenorphine. In some embodiments, the pharmaceutical composition comprises buprenorphine in an anhydrous form. In some embodiments, the pharmaceutical composition comprises a hydrate of buprenorphine. In some embodiments, the pharmaceutical composition comprises a hydrate of buprenorphine acetate. In some embodiments, the pharmaceutical composition comprises buprenorphine acetate tetrahydrate.
In some embodiments, the pharmaceutical composition comprises buprenorphine, a hydrate thereof, or a specific crystalline form thereof prepared by any of the foregoing methods for preparing compounds of formula (1), hydrates and crystalline forms thereof, as described herein, particularly in section 4.3 and the examples of the present disclosure.
In some embodiments, the pharmaceutical composition comprises buprenorphine, a hydrate thereof, or a particular crystalline form thereof, having impurity levels described herein, including impurity levels for compounds of formulae (10), (11), (12), (13), (14), and (15) as described herein.
In some embodiments, the pharmaceutical composition comprises buprenorphine free base prepared by the methods of the present disclosure.
In some embodiments, the pharmaceutical composition comprises buprenorphine free base having impurity levels described herein, including impurity levels for one or more of the compounds of formulae (10), (11), (12), (13), (14), and (15) as described herein.
As further described herein, the buprenorphine compounds and compositions of the present disclosure may be used, alone or in combination with other therapeutic agents, to treat a condition in an animal in need thereof. Thus, in some embodiments, the pharmaceutical compositions are formulated to contain the buprenorphine compounds of the present disclosure without other therapeutic agents. In other embodiments, the pharmaceutical compositions are formulated to contain a buprenorphine compound (first therapeutic agent) of the present disclosure and one or more additional therapeutic agents (e.g., one or more second therapeutic agents).
The pharmaceutical compositions of the present disclosure may take the form of solutions, suspensions, emulsions, tablets, pills, pellets, multiparticulates, capsules, liquid-containing capsules, powder-containing capsules, bead-or multiparticulate-containing capsules, lozenges, immediate release oral formulations, controlled release formulations, sustained release formulations, suppositories, aerosols, sprays, inhalation formulations, transdermal delivery systems (e.g., patches, aerosols, sprays, gels, salves, ointments), intraocular formulations, transmucosal delivery devices (e.g., for gingival, buccal, intranasal, rectal, vaginal or sublingual delivery), or any other form suitable for use. In some embodiments, the composition is in the form of a capsule (see, e.g., U.S. patent No. 5,698,155). Further examples of suitable pharmaceutical excipients are described in Radebough et al, "Preformulation," page 1447-1676 Remington's pharmaceutical sciences, Vol.2 (Gennaro eds., 19 th edition, Mack Publishing, Easton, PA, 1995), which is incorporated herein by reference.
In some embodiments, the pharmaceutical compositions of the present disclosure preferably comprise a suitable amount of one or more pharmaceutically acceptable excipients to provide a form that is appropriately administered to the animal by a particular route. Such pharmaceutical excipients may be selected from diluents, suspending agents, solubilizers, binders, disintegrants, buffers, glidants, preservatives, colorants, antioxidants, lubricants, and the like. The pharmaceutical excipients may be liquids, such as water or oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipient may be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants may be used. In a preferred embodiment, the pharmaceutically acceptable excipient is sterile when administered to an animal. Water is a particularly suitable excipient when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be used as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. If desired, the composition may also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate a particular dosage form are described in Handbook of pharmaceutical excipients, (am. pharmaceutical Ass' n, Washington, DC, 1986).
In some embodiments, the buprenorphine compound or pharmaceutical composition of the present disclosure is formulated for transdermal administration, such as by using a transdermal patch. Transdermal patches may comprise a buprenorphine compound of the present disclosure, for example, contained in a reservoir or matrix, and an adhesive that allows the transdermal device to adhere to the skin and also allows the buprenorphine compound of the present disclosure to be delivered from the transdermal device through the skin of the animal. In another embodiment, a transdermal patch may comprise, for example, a pharmaceutical composition comprising a buprenorphine compound of the present disclosure contained in a reservoir or matrix, and an adhesive that allows the transdermal device to adhere to the skin and also allows the pharmaceutical composition to be transferred from the transdermal device through the skin of an animal.
Suitable transdermal formulations are described in U.S. patent nos. 6,264,980, 6,344,211, RE41,408, RE41,489 and RE41,571; U.S. patent application publication nos. 2010/0119585 and 2014/0363487; and international patent publication nos. WO 2013/088254, WO 2014/090921 and WO 2014/195352, each of which is incorporated herein by reference. Suitable transdermal formulations comprise a buprenorphine (e.g. buprenorphine free base) impermeable backing layer and a pressure sensitive adhesive layer on the buprenorphine impermeable backing layer. The pressure-sensitive adhesive layer is a skin contact layer. The pressure-sensitive adhesive layer comprises a pressure-sensitive adhesive based on at least one polymer, an analgesically effective amount of buprenorphine free base or a pharmaceutically acceptable salt thereof, and a carboxylic acid. The carboxylic acid is present in an amount sufficient such that the analgesically effective amount of buprenorphine is dissolved in the carboxylic acid to form a mixture and such that the carboxylic acid-buprenorphine mixture forms dispersed deposits in the pressure sensitive adhesive layer. The carboxylic acid is selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid, and mixtures thereof. In one embodiment, the carboxylic acid is levulinic acid. In another embodiment, the pressure sensitive adhesive is based on silicone. In another embodiment, the pressure sensitive adhesive is silicone based and the carboxylic acid is levulinic acid.
In some embodiments, the buprenorphine is administered in a transdermal system to provide, for example, a dosing time interval of about 24 hours, a dosing time interval of about 3 days, or a dosing time interval of about 7 days. In some embodiments, the transdermal buprenorphine system may be formulated to administer buprenorphine, e.g., at a rate of from about 0.001mcg/h to about 50mcg/h, or from about 0.01mcg/h to about 40mcg/h, or from about 0.05mcg/h to about 30mcg/h, or from about 0.1mcg/h to about 20mcg/h, or from about 0.5mcg/h to about 10 mcg/h. In some embodiments, the transdermal buprenorphine system may be formulated to administer buprenorphine, e.g., at a rate of about 0.001mcg/h to about 5mcg/h, or about 0.01mcg/h to about 4mcg/h, or about 0.05mcg/h to about 3mcg/h, or about 0.1mcg/h to about 2mcg/h, or about 0.5mcg/h to about 1 mcg/h. In some embodiments, the transdermal buprenorphine system may be formulated to administer buprenorphine, e.g., at a rate of about 50mcg/h, about 40mcg/h, about 30mcg/h, about 20mcg/h, about 10mcg/h, about 5mcg/h, about 4mcg/h, about 3mcg/h, about 2mcg/h, about 1mcg/h, about 0.5mcg/h, about 0.1mcg/h, about 0.05mcg/h, about 0.01mcg/h, or about 0.001 mcg/h.
In some embodiments, the pharmaceutical composition is formulated for oral administration. Pharmaceutical compositions of the present disclosure to be delivered orally can be, for example, in the form of tablets, capsules, soft gelatin capsules (gelcaps), caplets, troches, aqueous or oily solutions, suspensions, granules, powders, emulsions, syrups, fast dissolving tablets (such as for sublingual delivery), fast dissolving strips (such as for buccal delivery), or elixirs. When buprenorphine or other (e.g., second) therapeutic agent is incorporated into an oral tablet, such tablets may be compressed, wet milled, enteric coated, sugar coated, film coated, multiple compressed, or multiple layered.
Pharmaceutical compositions for oral administration may contain one or more additional agents, such as sweetening agents, such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, oil of wintergreen, or cherry; a colorant; and preservatives, and stabilizers to provide a stable pharmaceutically palatable dosage form. Techniques and compositions for preparing solid oral dosage Forms are described in pharmaceutical dosage Forms: tablets (edited by Lieberman et al, 2 nd edition, Marcel Dekker, Inc., 1989 and 1990). Techniques and compositions for preparing Tablets (compression and moulding), Capsules (hard and soft gelatine) and pellets are also described in King, "tables, Capsules, and balls," 1553-. Liquid oral dosage forms may include aqueous and non-aqueous solutions, emulsions, and suspensions. Techniques and compositions for preparing liquid oral dosage Forms are described in pharmaceutical dosage Forms: dispersion Systems (edited by Lieberman et al, 2 nd edition, Marcel Dekker, Inc., 1996 and 1998).
When the buprenorphine or the second therapeutic agent is formulated for parenteral administration by injection (e.g., continuous infusion or bolus injection), the formulation may be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and such formulation may further comprise pharmaceutically necessary additives such as one or more buffers, stabilizers, suspending agents, dispersing agents and the like. When the formulation of the present disclosure is to be injected parenterally, it may, for example, be in the form of an isotonic sterile solution. The formulations may also be in powder (e.g., lyophilized) form suitable for reconstitution in the form of an injectable formulation.
In some embodiments, the pharmaceutical compositions of the present disclosure are suitable for intravenous administration. Typically, such compositions comprise a sterile isotonic aqueous buffer. If necessary, the composition may further comprise a solubilizer. Pharmaceutical compositions for intravenous administration may optionally contain a local anesthetic, such as benzocaine or prilocaine, to reduce pain at the site of injection. Generally, the ingredients are supplied separately or mixed together in unit dosage form, e.g., as a lyophilized dry powder or anhydrous concentrate in a sealed container (such as an ampoule or sachet) that indicates the amount of active agent. Where the pharmaceutical composition of the present disclosure is to be administered by infusion, it may be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. When the pharmaceutical compositions of the present disclosure are administered by injection, an ampoule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.
When the pharmaceutical composition of the present disclosure is to be administered by inhalation, it may be formulated as a dry aerosol, or as an aqueous or partially aqueous solution.
In some embodiments, the pharmaceutical compositions of the present disclosure can be delivered in vesicles, particularly liposomes (see Langer, "New Methods of Drug Delivery," Science249: 1527-353-.
In some embodiments, the pharmaceutical compositions of the present disclosure can be delivered in an immediate release form. In other embodiments, the pharmaceutical compositions of the present disclosure may be delivered in a controlled release system or a sustained release system. Controlled or sustained release pharmaceutical compositions may have the common goal of improving drug therapy compared to the results achieved by their non-controlled or non-sustained release counterparts. Advantages of controlled or sustained release compositions include prolonged activity of the drug, reduced dosage frequency and increased compliance. In addition, controlled or sustained release compositions can advantageously affect the onset of action or other characteristics, such as blood levels of buprenorphine and/or another therapeutic agent, and can therefore reduce the occurrence of adverse side effects.
Controlled or sustained release compositions may have an immediate release component that initially releases an amount of buprenorphine or another therapeutic agent to rapidly produce the desired therapeutic or prophylactic effect, and then gradually and continuously releases other amounts of buprenorphine or another therapeutic agent to maintain a degree of therapeutic or prophylactic effect over an extended period of time. In order to maintain a constant level of buprenorphine and/or another therapeutic agent in the body, the pharmaceutical composition may be adapted to release the active ingredient from the dosage form at a rate that will replace the amount of active agent that is metabolized and excreted by the body. Controlled or sustained release of the active ingredient can be triggered by any of a variety of conditions, including, but not limited to, a change in pH, a change in temperature, a concentration or availability of an enzyme, a concentration or availability of water, or other physiological conditions or compounds.
The controlled and sustained release means that may be adapted for use in accordance with the present disclosure may be selected from those known in the art. Examples include, but are not limited to, those described in U.S. Pat. nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms may be used to provide controlled release of one or both active ingredients orSustained release using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, multiparticulates, liposomes, microspheres, or combinations thereof to provide the desired release profile from different ratios. Suitable controlled or sustained release formulations known in the art, including those described herein, can be readily adapted for use with the active ingredients of the present disclosure. See also Goodson, "Dental Applications," Medical Applications of controlled Release, volume 2, Applications and Evaluation, Langer and Wise eds, CRC Press, Chapter 6, pp 115-138 (1984). Other controlled or sustained release systems discussed by Langer in the review may be adapted for use in accordance with the present disclosure. In some embodiments, a pump, such as Saudek et al, "A precision Trial of the programmable Implantable medical System for Insulin Delivery," New Engl.321: 574-579(1989)). In some embodiments, polymeric materials may be implanted, such as Langer et al, "Chemical and Physical Structure of Polymers as Carriers for controlled Release of Bioactive Agents: a Review, "j.macromol.sci.rev.macromol.chem.C23(1)：61-126(1983)。
When in an oral dosage form, in the form of a tablet or pill, the pharmaceutical compositions of the present disclosure may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing targeted release of a particular portion of the gastrointestinal tract, or providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound (osmotic agent) may also be suitable for compositions for oral administration. In these latter platforms, fluid from the environment surrounding the capsule is drawn in by the drive compound, which expands to displace the agent through an orifice in the wall of the dosage form. Such a delivery platform may provide a substantially zero order delivery profile as opposed to a spike profile of an immediate release formulation. Time delay materials such as glyceryl monostearate or glyceryl stearate may also be used. Oral compositions preferably include pharmaceutical grade standard excipients selected from, inter alia, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.
In some embodiments, the dosage form may further comprise at least one polymer. Examples of polymers include, but are not limited to, polymers comprising formula (C)6H12O5)n(where n is 3 to 7,500), poly (alkylene oxides) such as poly (ethylene oxide) and poly (propylene oxide), alkali metal carboxyalkyl celluloses (where the alkali metal is sodium or potassium and the alkyl group is methyl, ethyl, propyl or butyl), and ethylene-acrylic acid copolymers, ethylene-methacrylic acid copolymers or ethylene-ethylacrylic acid copolymers.
In some embodiments, the polymer is selected from the group consisting of polyalkylene oxides and carboxyalkyl celluloses. The polyalkylene oxide may be a member selected from the group consisting of polyoxymethylene, polyethylene oxide ("PEO"), and polypropylene oxide. The carboxyalkyl cellulose may be a member selected from the group consisting of alkali metal carboxyalkyl celluloses, sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodium carboxyethyl cellulose, lithium carboxymethylcellulose, sodium carboxyethyl cellulose, carboxyalkylhydroxyalkyl celluloses, carboxymethyl hydroxyethyl cellulose, carboxyethyl hydroxyethyl cellulose, and carboxymethyl hydroxypropyl cellulose.
In some embodiments, the PEO polymer in the dosage form is high molecular weight PEO, i.e., having at least 0.5 × 10 in one embodiment6And in another embodiment has a molecular weight of at least 1 × 106Up to 15 × 106Molecular weight of (2). PEO molecular weight is determined by rheological measurements such as disclosed in U.S. Pat. No. 8,075,872, column 6, lines 5-14, incorporated herein by reference. The high molecular weight PEO polymers have a viscosity at 25 ℃ of 4500cP to 17600cP measured on a 5 wt% aqueous solution using a model RVFBrookfield viscometer (spindle 2/rotational speed 2rpm), 400cP to 4000cP measured on a 2 wt% aqueous solution using a specified viscometer (spindle 1 or spindle 3/rotational speed 10rpm), or 1650cP to 10000cP measured on a 1 wt% aqueous solution using a specified viscometer (spindle 2/rotational speed 2 rpm).
Dosage forms containing polyalkylene oxide, particularly PEO, and more particularly high molecular weight PEO, each having a breaking strength of at least 500N, are advantageous because they cannot be ground in conventional grinding devices available to drug abusers, such as mortar and pestles, due to the hardness they impart to, for example, tablets. This virtually precludes oral or parenteral, especially intravenous or nasal, abuse. Tamper resistant non-millable dosage forms are disclosed, for example, in U.S. patent nos. 8,075,872, 8,114,383, 8,192,722 and 8,309,060, which are incorporated herein by reference.
In some embodiments, the carboxyalkyl cellulose polymer in the dosage form is selected so as to impart a gel-like quality to the open dosage form, thereby reducing the potential for abuse of the buprenorphine compound of the present disclosure in the dosage form due to the gel-like consistency via disturbing or hindering the rapid high pleasure obtained from the open dosage form. For example, the gel-like consistency when in contact with the mucosa prevents abuse of the open dosage form by minimizing absorption (e.g., in the nostrils) or provides considerable difficulty in injecting the open dosage form due to the high viscosity imparted to the open dosage form (e.g., due to difficulty in pushing the open dosage form through a syringe or pain upon administration).
The carboxyalkyl cellulose gelling agent may be added to the formulation in one embodiment at a gelling agent to buprenorphine compound ratio of the present disclosure of from about 1: 40 to about 40: 1 by weight, or from about 1: 1 to about 30: 1 by weight in another embodiment, or from about 2: 1 to about 10: 1 by weight in another embodiment, such that the dosage form forms a viscous gel after the dosage form has been opened, dissolved in an aqueous liquid (from about 0.5mL to about 10mL, and preferably from about 1mL to about 5mL of the aqueous liquid), such that the resulting mixture has a viscosity of at least about 10cP in one embodiment and at least about 60cP in another embodiment. In another embodiment, after the dosage form is opened, dissolved in an aqueous liquid (from about 0.5mL to about 10mL and preferably from about 1mL to about 5mL of the aqueous liquid), and then heated (e.g., to greater than about 45 ℃), the carboxyalkyl cellulose gelling agent causes the dosage form to form a viscous gel such that the resulting mixture has a viscosity of at least about 10cP in one embodiment and at least about 60cP in another embodiment. Anti-opening dosage forms containing a gelling agent are disclosed, for example, in U.S. patent nos. 7,842,307, 8,337,888, 8,524,275, 8,529,948 and 8,609,683, which are incorporated herein by reference.
4.6 methods of use
The buprenorphine compounds of the present disclosure are suitable for use in human and veterinary medicine. As further described herein, the buprenorphine compounds are useful for treating or preventing a condition in an animal in need thereof. When administered to an animal, the buprenorphine compound may be administered as a component of a composition comprising one or more pharmaceutically acceptable carriers or excipients. The composition may be administered by any convenient route and may also be administered with a second therapeutically active agent. Administration can be systemic or local.
In some embodiments, the method of administration includes, but is not limited to, intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal (e.g., via a patch), rectal, by inhalation, transmucosal, or topical (especially to the ear, nose, eye, or skin). The method of administration is left to the discretion of the practitioner. In some cases, administration will result in the release of the buprenorphine compound into the bloodstream. In other cases, administration will result in only local release of the buprenorphine compound.
In some embodiments, the buprenorphine compounds and pharmaceutical compositions of the present disclosure may be used to treat conditions known to be treated with buprenorphine, alone or in combination with other therapeutic agents. In some embodiments, the buprenorphine compounds and pharmaceutical compositions of the present disclosure are useful for treating a condition selected from pain and drug addiction. In addition, the buprenorphine compounds of the present disclosure may be used in combination with other opioids to help alleviate opioid adverse side effects, such as respiratory depression, gastrointestinal motility disorders (e.g., constipation), euphoria, and the like.
Thus, in some embodiments, the buprenorphine compounds of the present disclosure and pharmaceutically acceptable compositions thereof are useful for treating or preventing acute or chronic pain in an animal. Examples of pain that can be treated or prevented using buprenorphine include, but are not limited to, cancer pain, neuropathic pain, labor pain, myocardial infarction pain, pancreatic pain, colon pain, post-operative pain, headache, muscle pain, arthritis pain, and pain associated with periodontal disease including gingivitis and periodontitis.
In some embodiments, the buprenorphine compounds of the present disclosure and pharmaceutically acceptable compositions thereof may also be used to treat or prevent pain associated with inflammation or with inflammatory diseases in an animal. Such pain may occur where there is inflammation in the body tissue, which may be a local inflammatory response and/or a systemic inflammation. For example, the buprenorphine compounds may be used to treat or prevent pain associated with inflammatory diseases, including (but not limited to): organ transplant rejection; reoxygenation injury resulting from organ transplantation including, but not limited to, heart, lung, liver or kidney transplantation (see Grupp et al, "protective Hypoxia-reoxygenesis in the Absence of Poly (ADP-ribose) synthesized tissue damage Hearts," J.mol.cell cards.31: 297-303 (1999)); chronic inflammatory diseases of the joints including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome and Crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmia, and endophthalmitis; chronic inflammatory diseases of the gums including gingivitis and periodontitis; pulmonary tuberculosis; jatropha curcas; nephritic diseases including uremic complications, glomerulonephritis and nephropathy; inflammatory diseases of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and alzheimer's disease, infectious meningitis, encephalomyelitis, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis; autoimmune diseases, including type I and type II diabetes; the complication of the diabetes mellitus is that the medicine composition is used for treating the diabetes mellitus,including, but not limited to, diabetic cataracts, glaucoma, retinopathy, nephropathy (such as microalbuminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathy, autonomic neuropathy, gangrene of the foot, atherosclerotic coronary artery disease, peripheral artery disease, nonketotic hyperglycemic hyperosmolar coma, tibial plaques, joint problems, and skin or mucosal complications (such as infection, tibial plaque, candida infection, or diabetic lipogenic necrosis); immune-complex vasculitis and Systemic Lupus Erythematosus (SLE); inflammatory heart diseases such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and atherosclerosis; and various other diseases that may have significant inflammatory causes, including preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The buprenorphine compounds of the present disclosure may also be used to inhibit, treat or prevent pain associated with inflammatory diseases, which may for example be systemic inflammation of the body, such as gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock or shock induced by cancer chemotherapy in response to proinflammatory cytokines, such as shock associated with proinflammatory cytokines. The shock may be induced, for example, by a chemotherapeutic agent administered as a cancer treatment.
The buprenorphine compounds of the present disclosure, or pharmaceutically acceptable compositions thereof, may also be used to treat or prevent pain associated with or nerve injury (i.e., neuropathic pain). Chronic neuropathic pain is a heterogeneous disease state with unknown etiology. In chronic neuropathic pain, pain can be mediated by a variety of mechanisms. This type of pain is generally caused by damage to peripheral or central nervous tissue. Syndromes include pain associated with spinal cord injury, multiple sclerosis, post-herpetic neuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflex sympathetic dystrophy, as well as lower back pain. Chronic pain differs from acute pain in that for chronic neuropathic pain recipients, the allodynia can be described as spontaneous pain, persistent superficial burns and/or deep soreness. The pain may be caused by thermal, cold and mechanical hyperalgesia or by thermal, cold or mechanical allodynia.
Chronic neuropathic pain can be caused by injury or infection of peripheral sensory nerves. Including, but not limited to, pain resulting from peripheral nerve trauma, herpes virus infection, diabetes, burning pain, plexus avulsion, neuroma, amputation and vasculitis. Neuropathic pain can also be caused by nerve damage due to chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiency. Stroke (spinal cord or brain) and spinal cord injury can also induce neuropathic pain. Cancer-related neuropathic pain can be caused by tumor growth compression of adjacent nerves, brain or spinal cord. In addition, cancer treatments, including chemotherapy and radiation therapy, can cause nerve damage. Neuropathic pain includes, but is not limited to, pain caused by nerve damage, such as that experienced by a diabetic patient.
In some embodiments, the buprenorphine compounds of the present disclosure and pharmaceutical compositions thereof are useful for treating or preventing pain associated with osteoarthritis. Osteoarthritis (OA), also known as osteoarthrosis, degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving the degradation of joints, including articular cartilage and subchondral bone. Examples of OA that may be treated or prevented using the buprenorphine compounds of the present disclosure include, but are not limited to, joint pain, joint stiffness, joint tenderness, joint locking, and hydrarthrosis.
In some embodiments, the buprenorphine compounds of the present disclosure and pharmaceutical compositions thereof are useful in treating or preventing drug addiction or a condition of drug abuse, particularly drug addiction or drug abuse of another opioid. In some embodiments, the buprenorphine is administered concurrently with another opioid, wherein the buprenorphine, when administered at a relatively low dose, is useful in preventing, minimizing, inhibiting, ameliorating, or reversing the euphoria caused by the other opioid.
In some embodiments, the buprenorphine compounds of the present disclosure and pharmaceutical compositions thereof may be used to treat or prevent drug addiction or a condition of drug abuse of an opioid agonist selected from codeine, fentanyl, heroin, hydrocodone, hydromorphone, methadone, morphine, opium, oxycodone, oxymorphone, tramadol and mixtures of any of the foregoing.
In some embodiments, the buprenorphine compounds of the present disclosure and pharmaceutical compositions thereof may be used at relatively low doses to treat, ameliorate, minimize or prevent respiratory depression conditions caused by, inter alia, other opioids, such as, inter alia, morphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, and fentanyl, as disclosed in U.S. patent No. 8,946,253, which is incorporated herein by reference.
In some embodiments, the buprenorphine compounds of the present disclosure or pharmaceutical compositions thereof may be used at relatively low doses to treat, ameliorate, minimize or prevent conditions of intestinal motility disorders, such as reduced gastric motility, delayed gastric emptying, constipation, bloating, and colic. In particular, the buprenorphine compounds of the present disclosure or pharmaceutical compositions thereof may be used to treat conditions of intestinal motility disorders (e.g., opioid-induced constipation) caused by other opioids such as morphine, oxycodone, hydrocodone, and fentanyl.
The amount of the buprenorphine compound or pharmaceutically acceptable composition thereof effective to treat or prevent any of the conditions described herein can be determined by standard clinical techniques. The precise dose to be used will depend on the route of administration and the severity of the condition, and can be determined at the discretion of the medical practitioner, depending on the circumstances of the individual animal. However, suitable effective doses may range from about 0.01mg/kg body weight to about 2500mg/kg body weight in some embodiments. In some embodiments, the effective dose is between about 0.01mg/kg body weight to about 100mg/kg body weight of the buprenorphine compound; from about 0.02mg/kg to about 50mg/kg body weight in another embodiment; and in another embodiment from about 0.025mg/kg to about 20mg/kg of body weight.
In some embodiments, an effective dose is administered about every 24 hours, about every 12 hours, about every 8 hours, about every 6 hours, or about every 4 hours until the condition is discontinued.
In some embodiments, oral dosage forms may be formulated to administer a buprenorphine compound of the present disclosure, e.g., at a dose of less than about 500mg, less than about 400mg, less than about 350mg, less than about 300mg, less than about 250mg, less than about 200mg, less than about 150mg, less than about 100mg, less than about 90mg, less than about 80mg, less than about 70mg, less than about 60mg, less than about 50mg, less than about 40mg, less than about 30mg, less than about 20mg, less than about 10mg, less than about 9mg, less than about 8mg, less than about 7mg, less than about 6mg, less than about 5mg, less than about 4mg, less than about 3mg, less than about 2mg, less than about 1mg, less than about 0.9mg, less than about 0.8mg, less than about 0.7mg, less than about 0.6mg, less than about 0.5mg, less than about 0.4mg, less than about 0.3mg, less than about 0.2mg, or less than about 0.1 mg.
In some embodiments, the oral dosage form may be formulated to administer buprenorphine, for example, at a dose of from about 1mg to about 500mg, or from about 1mg to about 400mg, or from about 1mg to about 350mg, or from about 1mg to about 300mg, or from about 1mg to about 250mg, or from about 1mg to about 200mg, or from about 1mg to about 150mg, or from about 1mg to about 100mg, or from about 1mg to about 90mg, or from about 1mg to about 80mg, or from about 1mg to about 70mg, or from about 1mg to about 60mg, or from about 1mg to about 50mg, or from about 1mg to about 40mg, or from about 1mg to about 30 mg.
In some embodiments, oral dosage forms may be formulated to administer a buprenorphine compound of the present disclosure, for example, at a dose of from about 30mg to about 500mg, or from about 30mg to about 400mg, or from about 30mg to about 350mg, or from about 30mg to about 300mg, or from about 30mg to about 250mg, or from about 30mg to about 200mg, or from about 30mg to about 150mg, or from about 30mg to about 100mg, or from about 30mg to about 90mg, or from about 30mg to about 80mg, or from about 30mg to about 70mg, or from about 30mg to about 60mg, or from about 30mg to about 50mg, or from about 30mg to about 40 mg.
In some embodiments, oral dosage forms may be formulated to administer a buprenorphine compound of the present disclosure, for example, at a dose of from about 0.1mg to about 30mg, or from about 0.2mg to about 30mg, or from about 0.3mg to about 30mg, or from about 0.4mg to about 30mg, or from about 0.5mg to about 30mg, or from about 0.6mg to about 30mg, or from about 0.7mg to about 30mg, or from about 0.8mg to about 30mg, or from about 0.9mg to about 30mg, or from about 2mg to about 30mg, or from about 3mg to about 30mg, or from about 4mg to about 30mg, or from about 5mg to about 30mg, or from about 6mg to about 30mg, or from about 7mg to about 30mg, or from about 8mg to about 30mg, or from about 9mg to about 30mg, or from about 10mg to about 30 mg.
In some embodiments, oral dosage forms may be formulated to administer a buprenorphine compound of the present disclosure, for example, at a dose of from about 3mg to about 500mg, or from about 3mg to about 400mg, or from about 3mg to about 350mg, or from about 3mg to about 300mg, or from about 3mg to about 250mg, or from about 3mg to about 200mg, or from about 3mg to about 150mg, or from about 3mg to about 100mg, or from about 3mg to about 90mg, or from about 3mg to about 80mg, or from about 3mg to about 70mg, or from about 3mg to about 60mg, or from about 3mg to about 50mg, or from about 3mg to about 40mg, or from about 3mg to about 30mg, or from about 3mg to about 20mg, or from about 3mg to about 10 mg.
In some embodiments, oral dosage forms may be formulated to administer a buprenorphine compound of the present disclosure, e.g., at a dose of from about 0.1mg to about 3mg, or from about 0.2mg to about 3mg, or from about 0.3mg to about 3mg, or from about 0.4mg to about 3mg, or from about 0.5mg to about 3mg, or from about 0.6mg to about 3mg, or from about 0.7mg to about 3mg, or from about 0.8mg to about 3mg, or from about 0.9mg to about 3mg, or from about 1mg to about 3mg, or from about 2mg to about 3 mg.
In some embodiments, the buprenorphine compounds of the present disclosure are administered sublingually. The buprenorphine compound may be formulated in a sublingual formulation to provide, for example, a dosing time interval of about 4 hours, a dosing time interval of about 6 hours, a dosing time interval of about 8 hours, a dosing time interval of about 12 hours, or a dosing time interval of about 24 hours.
In some embodiments, the sublingual formulation may be formulated for administration of the buprenorphine compounds of the present disclosure, for example, at a dose of from about 0.001mg to about 10mg, or from about 0.01mg to about 8mg, or from about 0.05mg to about 6mg, or from about 0.1mg to about 5mg, or from about 0.5mg to about 4mg, or from about 1mg to about 2 mg.
In some embodiments, the buprenorphine compounds of the present disclosure are administered in a transdermal system to provide a dosing time interval of, for example, about 24 hours, about 3 days, or about 7 days.
In some embodiments, the transdermal system may be formulated to administer buprenorphine, e.g., at a rate of from about 0.001mcg/h to about 50mcg/h, or from about 0.01mcg/h to about 40mcg/h, or from about 0.05mcg/h to about 30mcg/h, or from about 0.1mcg/h to about 20mcg/h, or from about 0.5mcg/h to about 10 mcg/h.
In some embodiments, the transdermal system may be formulated to administer buprenorphine, e.g., at a rate of from about 0.001mcg/h to about 5mcg/h, or from about 0.01mcg/h to about 4mcg/h, or from about 0.05mcg/h to about 3mcg/h, or from about 0.1mcg/h to about 2mcg/h, or from about 0.5mcg/h to about 1 mcg/h.
In some embodiments, the transdermal system may be formulated to administer buprenorphine, e.g., at a rate of about 50mcg/h, about 40mcg/h, about 30mcg/h, about 20mcg/h, about 10mcg/h, about 5mcg/h, about 4mcg/h, about 3mcg/h, about 2mcg/h, about 1mcg/h, about 0.5mcg/h, about 0.1mcg/h, about 0.05mcg/h, about 0.01mcg/h, or about 0.001 mcg/h.
In some embodiments, the buprenorphine compounds of the present disclosure may be administered by any route (e.g., orally, transdermally, transmucosally, or subcutaneously) to provide, for example, from about 0.001mg/kg to about 1mg/kg, or from about 0.005mg/kg to about 0.5mg/kg, or from about 0.05mg/kg to about 0.1mg/kg at steady state. In other embodiments, the buprenorphine compound may be administered by any route (e.g., orally, transdermally, transmucosally, or subcutaneously) to provide, for example, about 1mg/kg, about 0.5mg/kg, about 0.1mg/kg, about 0.05mg/kg, about 0.005mg/kg, or about 0.001mg/kg at steady state. Where buprenorphine is used in combination with another therapeutic agent, the buprenorphine compound of the present disclosure may be administered for any suitable time, for example for the entire duration of the therapy with the other agent, or for a portion of the entire duration of the therapy with the other agent.
In some embodiments, buprenorphine compounds of the present disclosure may be administered by any route (e.g., orally, transdermally, transmucosally, or subcutaneously) to provide a C of, e.g., about 0.001ng/mL to about 15ng/mL, or about 0.005ng/mL to about 12ng/mL, or about 0.05ng/mL to about 10ng/mL, or about 0.05ng/mL to about 1ng/mL, or about 0.05ng/mL to about 0.5ng/mL, about 0.5ng/mL to about 8ng/mL, or about 1.0ng/mL to about 5ng/mL, or about 2ng/mL to about 4ng/mL, after the first administration or at steady statemax。
In some embodiments, the buprenorphine compounds of the present disclosure may be administered by any route (e.g., orally or transdermally or subcutaneously) to provide, for example, about 0.001ng/mL, b,C of about 0.01ng/mL, about 0.1ng/mL, about 1ng/mL, about 2ng/mL, about 3ng/mL, about 4ng/mL, or about 5ng/mLmax。
In some embodiments, buprenorphine compounds of the present disclosure may be administered by any route (e.g., orally, transdermally, transmucosally, or subcutaneously) to provide, for example, less than about 5ng/mL, less than about 4ng/mL, less than about 3ng/mL, less than about 2ng/mL, less than about 1ng/mL, less than about 0.1ng/mL, less than about 0.01ng/mL, less than about 0.001ng/mL, or less than about 0.0001ng/mL of C after the first administration or at steady statemax。
In some embodiments, the buprenorphine compounds of the present disclosure may be administered by any route (e.g., orally, transdermally, transmucosally, or subcutaneously) to provide an AUC, e.g., of about 0.01ng/mL per hour to about 100ng/mL per hour, or about 0.1ng/mL per hour to about 75ng/mL per hour, or about 1.0ng/mL per hour to about 50ng/mL per hour, or about 5.0ng/mL per hour to about 40ng/mL per hour, or about 10ng/mL per hour to about 30ng/mL per hour, after the first administration or at steady state.
In some embodiments, the steady state or first administration AUC and C disclosed hereinmaxValues may be obtained by any suitable route of administration, such as transdermal, transmucosal, sublingual, buccal, oral, subcutaneous, intramuscular, or parenteral. Depot injections of buprenorphine may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. In such formulations, the release of buprenorphine may be controlled by having suitable polymeric or hydrophobic materials (e.g. polylactic glycolic acid), ion exchange resins or formulations from sparingly soluble derivatives (e.g. sparingly soluble salts). In some embodiments, the depot injection provides an administration time interval of about 1 day to about 3 months, or about 3 days, about 7 days, about 10 days, about 14 days, about 21 days, about 1 month, about 6 weeks, or about 2 months.
In some embodiments, the methods for treating or preventing a condition in an animal in need thereof can further comprise co-administering to the administered animal a buprenorphine compound or composition of the disclosure (i.e., a first therapeutic agent), a second therapeutic agent. In some embodiments, the second therapeutic agent is administered in an effective amount.
The compositions of the present disclosure are prepared by a method comprising admixing a buprenorphine compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier or excipient. Blending can be accomplished using methods known for blending compounds with pharmaceutically acceptable carriers or excipients. In one embodiment, buprenorphine prepared from the acetate salt is present in the composition in an effective amount.
Throughout this disclosure, when referring to the buprenorphine free base, the acetate salt of buprenorphine, the hydrate of buprenorphine acetate, the buprenorphine acetate tetrahydrate, and/or the weight% of various impurities, the weight% is determined via HPLC purity, for example by the method of example 7 set forth herein.
The following examples are set forth to aid in understanding the present disclosure and should not be construed to specifically limit the invention described and claimed herein. Such variations (including substitutions of all equivalents now known or later developed) and modifications in the formulation or design of experiments which would come within the purview of those skilled in the art are to be considered as falling within the scope of the invention incorporated herein.
5. Examples of the embodiments
Various features and embodiments of the present disclosure are illustrated in the following representative examples, which are intended to be illustrative and not limiting.
Example 1: acid screening experiments with buprenorphine free base
Buprenorphine free base may be considered an organic amine/phenol which can be treated with an acid or base to form its corresponding ammonium salt or phenolate salt. Which may facilitate the formation of such salts for purification purposes due to differences in physical properties (e.g., solubility) between the salt of the product and the target impurity. The purified salt may then be treated with a base (or acid for phenates) to regenerate the desired buprenorphine free base.
Buprenorphine was purified via the hydrochloride salt. The conversion of buprenorphine free base to its hydrochloride salt and back to the free base was explored. No significant clearance of the compound of formula (12) or the compound of formula (14) was observed under any of the conditions explored.
To further expand the study of the purification of buprenorphine free base via salt formation, other acids were explored. These acids include acetic acid, formic acid, trifluoroacetic acid, phosphoric acid, tartaric acid, toluenesulfonic acid, propionic acid and methanesulfonic acid. With respect to the screening of these other acids, the removal of only the impurity compound of formula (12) was investigated.
Procedure for acid screening experiments. In a 20mL scintillation vial, buprenorphine free base (1.0g) is dissolved or suspended in water, an organic solvent or a mixed organic and aqueous solvent, followed by addition of an acid. If dissolution is necessary, the mixture is heated in a cake-type (pie-block) heating system up to 80 ℃ and slowly cooled to a temperature of about 25 ℃. If a crystalline material, i.e. a buprenorphine salt, is observed, the solid is filtered, washed with water and dried in an oven at 80 ℃ for about 16 hours at sub-atmospheric pressure and the% recovery relative to the initial 1.0g buprenorphine free base feed is determined. Table 3 summarizes the results. With respect to acids that are solid at a temperature of about 20 ℃, i.e., tartaric acid and toluenesulfonic acid hydrate, the mass of acid used is provided rather than the acid volume.
Table 3: acid screening experiments with buprenorphine free base
Figure BDA0001463758400001021
Figure BDA0001463758400001031
Acetic acid or formic acid causes the formation of crystals; the addition of other acids did not form filterable salts. However, in order to achieve crystallisation of the buprenorphine salt when acetic acid or formic acid is used, it has been found that the volume of water used should be about the same as the volume of acid used to promote dissolution of the buprenorphine free base. Thereafter, the addition of larger amounts of water causes crystallization of the buprenorphine salt. For example, with respect to the addition of acetic acid to achieve 80% recovery in table 3 above, 2.5mL of acetic acid and 2.5mL of water were initially added, making it possible for the buprenorphine free base to dissolve. Thereafter, a further 12.5mL of water was added at a temperature of about 25 ℃ to cause crystallisation of the buprenorphine acetate.
In addition, only two aqueous mixtures containing acetic acid or formic acid provide a promising clean-up (up to 40%) of the impurities of the compound of formula (12). Recovery of the corresponding salt of buprenorphine was higher in the aqueous mixture of acetic acid (78.5%, average of four determinations) than in formic acid (61%). In both cases, the corresponding salt of buprenorphine is isolated as a crystalline solid. Other acids provide the corresponding salt of buprenorphine (if present) as an oil or gum that cannot be separated via filtration. Interestingly, it was found that the solids separated from the acetic acid: water, when dried at elevated temperatures (e.g., 85 ℃) at sub-atmospheric pressure, produced buprenorphine free base. Without being bound by theory, it is believed that this finding suggests a slightly weaker association between acetic acid and buprenorphine and that this phenomenon develops into an advantageous separation of buprenorphine free base by a purification procedure involving aqueous acetic acid (see, e.g., examples 2 and 8 below). Repeated acid screening assays with respect to the acetic acid: water solvent system demonstrated that crystallization from acetic acid: water resulted in favorable increased clearance of the compound of formula (12).
Example 2: preparation of buprenorphine acetate
To prepare the buprenorphine acetate, buprenorphine free base (100g, 214mmol) was dissolved in 1: 1 acetic acid: water (vol: vol, 370 mL). The temperature during the addition of the acetic acid-water solution was maintained at 60 ℃. Still at 60 ℃, the mixture is then fine filtered, i.e., filtered, to remove non-product related insoluble impurities (e.g., dust). The dissolution apparatus was then rinsed with 0.4 volumes of water containing 51 wt% acetic acid and the rinse and filtrate combined.
And (3) crystallization: at 60 ℃, about 0.75 volume (75mL) of water (anti-solvent) was added to the combined filtrate at a rate of 8 mL/min. The resulting blend was inoculated with 0.5g crystals of buprenorphine acetate. The solution was held at 60 ℃ for 0.5h, and then about 5.9 volumes (588mL) of water (anti-solvent) were added at a rate of about 15mL/min at a temperature of 60 ℃. Thereafter, about 0.9 volume (88mL) of IPA was added at a temperature of 60 ℃ and the mixture was cooled to 20 ℃ at a rate of 8 ℃/h to provide a precipitate.
Isolation of buprenorphine acetate: the precipitate from the crystallization step was filtered and washed with 2.5 volumes of water containing 17 wt% IPA. The precipitate was then washed again with water containing 17 wt% IPA at 20 ℃.
Example 3: determination of buprenorphine acetate tetrahydrate Crystal Structure by Single Crystal X-ray analysis
Colorless prismatic [ C ] of appropriate size 0.24mm × 0.10mm × 0.05mm obtained by a method substantially equivalent to that of example 2 but modified to promote growth of larger size crystals29H42NO4]+[CH3COO]-·4H2The O single crystal was mounted on MICROMOUNT and centered on an R-AXIS RAPID X-ray diffractometer (Rigaku America, Woodlands, TX).
Copper source equipped with sealed tube at temperature of about 25 deg.C
Figure BDA0001463758400001051
And acquiring diffraction data on the diffractometer of the Spider curved surface imaging plate detector. Four frames separated in reciprocal space are recorded to provide the orientation matrix and initial cell parameters. The final cell parameters were obtained and refined based on the complete data set. Using 5 ° oscillating steps and 300s exposure for each frame to
Figure BDA0001463758400001052
The resolution yields a diffraction data set of reciprocal space. Integration of the intensities and refinement of the unit cell parameters were achieved using CRYSTALCLEAR software. The observation of the crystals after data collection and the appearance of the diffraction rings on the recorded images indicate that the crystals underwent slow decomposition during the diffraction experiments.
SOLVE structure resolution program (Puschmann et al, "[ MS 45-P09)]Olex2-acomplete package for molecular crystallography，”Acta Cryst.A69: s679(2013)) OLEX2 (dolmenov et al, "OLEX 2: a complete structure solution, redefinition and analysis program, "J Appl Crystal.42: 339-odern computingenvironment-Olex2 dissected，”Acta Cryst.A71: 1-17(2014)) are refined using Gaussian-Newton (Gauss-Newton) full matrix minimization.
Analyzing the structure based on system extinction (systematic absence) and intensity statistics and at non-centrosymmetric monoclinic P21And (4) performing calculation in the space group. Non-hydrogen atoms were found by a charge inversion method for resolving the structure and refined using anisotropic atom displacement parameters. The hydrogen atoms were placed in the calculated positions and refined with isotropic atom shift parameters. The structure has two buprenorphine cations and two acetate anions and eight water molecules in a unit cell, such that one buprenorphine cation, one acetate anion and four water molecules are independently symmetric.
The stacking of molecules in the crystal is determined by the strong coulombic interaction between the buprenorphine cation and the acetate anion, and nine different hydrogen bonds ("HB") between the buprenorphine cation, the acetate anion, and the water molecule.
Three strong HBs are present in the structure. One HB (represented by "a" in fig. 1) is an intramolecular hydrogen bond between the aliphatic hydroxyl group (containing the oxygen atom labeled "O23" in fig. 3) and the oxygen atom of the methoxy group (labeled "O21" in fig. 3) of buprenorphine; intramolecular HB length of
Figure BDA0001463758400001061
Another HB (denoted by "B" in fig. 1) is an intermolecular HB formed between the hydrogen of the nitrogen cation of buprenorphine (HB donor, labeled "N1" in fig. 3) and one oxygen atom of the acetate anion (HB acceptor, labeled "O42B" in fig. 3); intermolecular HB length of
Figure BDA0001463758400001062
The third HB (denoted by "C" in fig. 1) is another intermolecular HB between the water molecule oxygen (labeled "O1" in fig. 3) and the phenol group (HB donor, containing the oxygen atom labeled "O11" in fig. 3). The length of the bond is
Figure BDA0001463758400001063
Indicating a strong interaction.
Acetate anions are also involved in the formation of other HBs with adjacent water molecules. The HB distance of these three interactions is
Figure BDA0001463758400001064
(acetate anions with water molecules containing O1),
Figure BDA0001463758400001066
(also with a water molecule containing O1 from another water molecule) and
Figure BDA0001463758400001065
(hydrogen of acetate anion with water molecule containing oxygen atom labeled "O4" in FIG. 3).
The aliphatic hydroxyl group of buprenorphine also serves as an HB acceptor, forming an HB, represented by "D" in fig. 1, with the adjacent water molecule (containing O4) serving as an HB donor. The HB length of this interaction is
Figure BDA0001463758400001068
Significantly longer than the intramolecular hydrogen bond a.
The phenol group is also involved in the formation of two intramolecular hydrogen bonds (both with adjacent water molecules). One of the two hydrogen bonds (HB with oxygen atom O1 previously identified as "C" in FIG. 1) with HB formed by the oxygen atom labeled "O2" in FIG. 3
Figure BDA0001463758400001067
Is obviously shorter than
Figure BDA00014637584000010610
Figure BDA0001463758400001069
And is therefore stronger.
All four water molecules are involved in the formation of different hydrogen bonds; three of them are saturated, i.e., three HB each are formed-two as donors and one as acceptor. One water molecule (containing the oxygen atom labeled "O3" in fig. 3) was involved in the formation of only one HB (with another water molecule containing O2). Without being bound by theory, it is believed that the water molecule containing O3, which is the loosest combination of four water molecules, will most easily leave the crystal lattice during the dehydration process.
Water molecule 1 (containing O1) forms two HBs with two acetate anions and accepts HB from the phenolic hydroxyl group of buprenorphine. Water molecule 2 (containing O2) forms two HB with two other water molecules and one acts as a donor with phenolic hydroxyl groups. Water molecule 3 (containing O3) as donor forms only one HB with another water molecule (containing O2). The water molecule 4 (containing O4) forms one hydrogen bond with the acetate anion, which has the aliphatic hydroxyl group of buprenorphine and accepts HB from another water molecule (containing O2).
The density of the crystalline phase at a temperature of about 25 ℃ was calculated to be 1.2535g/cm3。
Table 4 summarizes some single crystal X-ray analytical determinations for buprenorphine acetate tetrahydrate. Figure 2 shows a stack of buprenorphine acetate tetrahydrate in a unit cell.
TABLE 41
Figure BDA0001463758400001071
Figure BDA0001463758400001081
1Each number in brackets is the estimated standard deviation ("ESD") of the last digit of the reported value. For example, for the reported unit cell parameter, the a-axis length is
Figure BDA0001463758400001082
ESD is
Figure BDA0001463758400001083
The single crystals of buprenorphine acetate tetrahydrate analyzed had the atomic fraction coordinates set forth in table 5 (× 10)4) And equal isotropic displacement parameter
Figure BDA0001463758400001084
Figure 3 shows a stick schematic of the components of the buprenorphine acetate tetrahydrate crystal, including the atomic numbering scheme used in table 5.
TABLE 51
Figure BDA0001463758400001085
Figure BDA0001463758400001091
1Each number in brackets is the ESD of the last digit of the reported value.
Example 4: buprenorphine acetate tetrahydrate structures by X-ray powder diffraction
To further characterize the crystalline form of buprenorphine acetate tetrahydrate, the powdered compound was analyzed by X-ray diffraction. Representative XRPD patterns obtained from buprenorphine acetate tetrahydrate samples using cuka radiation yielded peaks at diffraction angles (° 2 θ ± 0.2 °) provided in table 1 above and shown in figure 4.
The XRPD pattern was collected by an X' Pert PRO MPD diffractometer (PANalytical inc., Westborough, MA) using an incident beam of Cu radiation generated using an OPTIX long fine focus source. An elliptical graded multilayer mirror is used to focus CuK α X-rays through the sample and onto the detector. Prior to analysis, silicon samples (National Institute of standards and Technology ("NIST") standard reference material 640d, Gaithersburg, MD) were analyzed to verify that the observed Si 111 peak position was consistent with the NIST-confirmed position. Samples of the samples were sandwiched between 3 μm thick films and analyzed for transmission geometry. The short anti-scatter extensions and anti-scatter-blade edges of the light shield serve to minimize the background generated by air. The soller slits with respect to the incident and diffracted beams serve to minimize broadening from axial divergence. Diffraction patterns were collected using an X 'Celerator scanning position sensitive detector (PANalytical Inc.) and X' Pert receipt collection software version 2.2b located at 240mm from the test specimen.
Example 5: differential scanning calorimetry analysis of buprenorphine acetate tetrahydrate
To further characterize the buprenorphine acetate tetrahydrate, the compound was analyzed by differential scanning calorimetry ("DSC"). A representative DSC curve of a buprenorphine acetate tetrahydrate sample is shown in figure 5.
The DSC of the buprenorphine acetate tetrahydrate sample presented as heat flow (W/g) versus temperature (c) has two transition regions. The first transition zone is from about 50 ℃ to about 180 ℃. The one or more peaks in this region are broad peaks with one or more minima and may represent water and/or acetic acid lost from the material sample analyzed. The second transition region is from about 210 ℃ to about 225 ℃. This region provides a sharp transition that may represent melting of buprenorphine base. This sharp transition is also present at about the same peak temperature in the DSC of the free base form of buprenorphine.
Several samples of buprenorphine acetate tetrahydrate of different sizes were analyzed for consistency between different sample sizes. DSC analysis was performed using a linear heating ramp of 10 ℃/min to 250 ℃. The measurement results were determined with a Q20DSC apparatus (TAInstructions, New Castle, DE). The integral (area under the curve) of the transition region (region 1/region 2) was determined by the tai instruments general analysis 2000 software (version 4.5A, build 4.5.0.5) in a temperature range of about 35 ℃ to about 180 ℃ for the first transition region and about 203 ℃ to 233 ℃ for the second transition region. The integral ratio of the transition region is shown in table 6 below. A representative DSC curve for batch 2, discussed below, is shown in figure 6. As can be noted from fig. 6, for this assay, zone 1 extends from point "a" at about 35.5 ℃ to point "B" at about 178 ℃ and zone 2 extends from point "C" at about 206 ℃ to point "D" at about 231 ℃.
TABLE 6
Figure BDA0001463758400001111
To test the consistency of this integral ratio between buprenorphine acetate tetrahydrate samples, several different sample batches were analyzed. DSC analysis was performed using a linear heating ramp of 10 ℃/min to 250 ℃. The results are shown in Table 7.
TABLE 7
Figure BDA0001463758400001112
Figure BDA0001463758400001121
The integral ratio of the two regions was similar over a range of sample sizes. The integral ratio of the two regions was similar over multiple samples of buprenorphine acetate. The approximate integral ratio for region 1/region 2 of the buprenorphine acetate tetrahydrate samples was 7.0 to about 8.0. In another embodiment, the approximate integral ratio for region 1/region 2 of the buprenorphine acetate tetrahydrate sample is from 7.1 to about 7.9. In another embodiment, the approximate integral ratio for region 1/region 2 of the buprenorphine acetate tetrahydrate sample is from 7.1 to about 7.7.
Example 6: buprenorphine acetate tetrahydrate karl fischer% water analysis
The water content of 13 samples of buprenorphine acetate tetrahydrate was measured by karl fischer ("KF") titration analysis. KF analysis methods are known in the art, see, for example, ASTM Standard E203-08 ("Standard test method for Water Using Volumetric Karl Fischer Titration") and ISO 760: 1978 ("Determination of Water-Karl Fischer Method"). A compilation of KF values for each sample of buprenorphine acetate tetrahydrate is tabulated below. The table represents a variety of samples that were generated from a variety of crystallization conditions and dried to constant weight at a temperature of about 25 ℃ and a pressure of about 1 atm. KF titration was performed using a 915 KF Ti-Touch device (Metrohm USA Inc., Riverview, FL) with HYDRANAL Complex 5 Karl Fischer reagent (Sigma-Aldrich, St. Louis, Mo.). The results are shown in table 8 below. The average of the 13 determinations is also provided in table 8, along with the theoretical weight percent water calculated for the tetrahydrate of buprenorphine acetate (12.02 wt%).
TABLE 8
Figure BDA0001463758400001131
The average of the weight% water of the 13 different buprenorphine acetate hydrate samples tested differed from this theoretical value by only 0.25 weight% water or only about 2.1%.
Example 7: HPLC analysis program
Waters 2695 HPLC (Waters Corp., Milford, Mass.) was used with a 100mm by 3.0mm internal diameter GEMINI NX-C18 column (3.0 μm particle size) (Phenomenex, Torrance, Calif.) reverse phase. The detection wavelength was 240 nm. Gradient mobile phase a 20mM aqueous ammonium bicarbonate solution at pH 9.0 ("MPA", 99.5%, Fluka, st.louis, MO) and acetonitrile ("MPB", 99.9%, Sigma-Aldrich, st.louis, MO) as mobile phase B were used according to the gradient curve provided in table 9.
TABLE 9
Figure BDA0001463758400001132
Figure BDA0001463758400001141
The column temperature was 40 ℃, the injection volume was 15 μ L, and the flow rate was 1.0 mL/min. Analysis ended at about 45 minutes after each injection.
Samples of each buprenorphine acetate tetrahydrate were prepared for HPLC analysis as follows. 100.0. + -. 2.0mg of sample are weighed in duplicate and the weight (W) is recordedSWeight of each sample) and quantitatively transferring the samples to 100mL volumetric flasks. Approximately 50mL of methanol (99.9%, Fisher Scientific, Pittsburgh, Pa.) was added to the flask and the blend was sonicated and/or vortexed as necessary until all solids appeared to be dissolved. Thereafter, additional methanol was added to the mark and the solution was mixed well.
Standard solutions were prepared as follows. Working standard solution was prepared by weighing 27.0 + -1.0 mg USP buprenorphine hydrochloride CI of known purityII reference standard (#1078700, USP, Rockville, Md.), record weight (W)STDWeight of USP standard corrected for purity) and quantitatively transferred to a 25mL volumetric flask. Approximately 15mL of methanol was added to the flask and the blend was sonicated and/or vortexed as necessary until all solids appeared to be dissolved. Thereafter, additional methanol was added to the mark and the solution was mixed well. The working standard solution contained the equivalent of 1.0mg/mL buprenorphine free base. The working standards were used to verify that the reproducibility of, inter alia, the retention time, tailing factor and buprenorphine peaks was acceptable. The intermediate standard solution was prepared by pipetting 2.5mL of the working standard solution into a 50mL measuring flask, diluting to volume with methanol and mixing well. The intermediate standard solution contained the equivalent of 0.05mg/mL buprenorphine free base. Sensitive standard solutions were prepared by pipetting 1.0mL of the intermediate standard solution into a 100mL measuring flask, diluting to volume with methanol and mixing well. The sensitivity standard solution contained the equivalent of 0.0005mg/mL buprenorphine free base. The sensitivity standard was used to verify that the HPLC signal to noise ratio was not less than 10.
System suitability standards were prepared as follows. To a container containing 10mg of the material of the European pharmacopoeia reference standard "buprenorphine for system suitability" (# Y0001122, European director for the Quality of the medicines & Health Care, Strasbourg, France) was added about 2mL of methanol. The container was capped, shaken and inverted several times to rinse it and dissolve all solids, and the solution was transferred to a 10mL measuring flask. This dissolution procedure was repeated two more times. Sonication of about 6mL of solution was continued for about 5min to ensure all solids were dissolved, cooled to a temperature of about 25 ℃, diluted to volume with methanol, and mixed well. System suitability standard solutions contain 1.0mg/mL buprenorphine free base together with impurities of known profile (see european pharmacopoeia monograph 1180, 1181). The system suitability standard was used to verify that the desired resolution was achieved between the impurity peak and the buprenorphine peak.
The HPLC column was cleaned and rinsed if necessary and then equilibrated with 80: 20 MPA: MPB at 40 ℃ and a flow rate of 1.0mL/min for 30 minutes. Thereafter, the injection sequence in table 10 was followed.
Watch 10
Figure BDA0001463758400001151
For each sample peak, the corresponding peak area was determined by the instrument software to provide amount AS. The total peak area A was determined again by the instrument software by summing the areas of all peaksGeneral assemblyIf the area of any peak is less than or equal to 0.05 × AGeneral assemblyThen from AGeneral assemblyRemove the area of the peak and repeat the process until no contribution of the trace peak from AGeneral assemblyAnd (5) removing. Thereafter, from A for this peakSAnd AGeneral assemblyFor example with respect to the area% purity of the buprenorphine acetate tetrahydrate peak (see, e.g., tables 11-14 in example 8) and calculated according to equation 1 as follows:
Figure BDA0001463758400001161
similarly, for each impurity peak, the peak is represented by A for that impurity peakSAnd AGeneral assemblyThe area% purity for this impurity peak was determined (see, e.g., tables 2 and 16) and calculated using the equation above. Area% purity for buprenorphine free base (see, e.g., table 16 in example 9) was also determined in this manner by replacing the buprenorphine tetrahydrate sample with the buprenorphine free base sample.
In certain instances, the weight% purity of buprenorphine free base is determined by the HPLC analytical procedure described above (see, e.g., table 15 in example 9). Quantification of buprenorphine free base was achieved by comparing its reaction to the HPLC reaction of USP buprenorphine hydrochloride CIII external reference standard described above. The weight% purity was calculated according to equation 2 below:
Figure BDA0001463758400001162
wherein:
AS*peak area of buprenorphine free base in the sample,
ASTDthe average peak area of the working standard used for quantification,
WS*(ii) the weight of buprenorphine free base in the sample (in mg), and
WSTDweight of standard (in mg) corrected for purity.
In equation 2, the amount "4" is the dilution factor; amount "0.9277" is the molecular weight ratio of buprenorphine free base to buprenorphine hydrochloride standard; and the quantity "100" is the conversion factor used to obtain percent purity.
The quantitative determination of impurities or unknowns in a sample is achieved by calculating its weight% in the sample according to equation 4 below:
Figure BDA0001463758400001171
wherein:
AI/Upeak area of impurities or unknowns in the sample,
WI/U(weight in mg) of sample containing impurities or unknowns), and
RRFI/Urelative response factor for impurities or unknowns.
In equation 3, the quantity ASTDAnd WSTDAs defined above for equation 2. Relative response factor (e.g. RRF)I/U) Is determined in a customary manner by methods known in the art; see, e.g., Gordon et al, "Relative response factor for Lamivudine and Zidovudine Related substructures by RP-HPLC with DADDelection", chem.6(12)：160-165(2014)。
The calculations of equations 1, 2 and 3 were automated by EMPOWER software provided with the Waters HPLC instrument used in this example.
Example 8: stability analysis of buprenorphine acetate tetrahydrate
Samples of buprenorphine acetate tetrahydrate were analyzed initially and after 1 and 3 months of aging. Each test sample was prepared by weighing approximately 300mg of the buprenorphine acetate tetrahydrate sample obtained by the method described in example 2 into a stability bag transparent to visible and UV light (ARMORFLEX, model SB4016-01, ILC Dover, Frederica, DE). The bags were sealed using a heated bag sealer. After exposure to one of the stability test conditions specified below, the samples were removed and analyzed for area% purity by HPLC as described in example 7.
Duplicate results for each aged sample were averaged to give the area% purity results reported in tables 11 to 14 below.
The long term aging stability for buprenorphine acetate tetrahydrate was determined in the dark at 25 ℃ and 60% humidity in a stability chamber. Samples were examined over periods of 0, 1 and 3 months. The results are shown in Table 11.
TABLE 11
Figure BDA0001463758400001181
Buprenorphine acetate tetrahydrate is stable without deterioration for up to 3 months under long term aging conditions.
The accelerated aging stability with respect to buprenorphine acetate tetrahydrate was examined in the dark under stability chamber conditions of 40 ℃ and 75% humidity. Samples were examined over periods of 0, 1 and 3 months. The results are shown in Table 12.
TABLE 12
Figure BDA0001463758400001182
Buprenorphine acetate tetrahydrate is stable without deterioration for up to 3 months under accelerated aging conditions.
The light stability with respect to buprenorphine acetate tetrahydrate was examined in a Caron stability chamber at 25 ℃ and 60% humidity. To test the aging stability in UV light, the samples were exposed continuously to UV light from a UV light source at 21.9W/m2TL20W/12RS UV bulb (Philips Lighting) at an intensity for periods of 0, 1 and 3 months. Is composed ofThe aging stability in visible light was tested by exposing samples continuously to visible light from an F24T12/CW/HO fluorescent light bulb (Philips Lighting) at an intensity of 27K lux for periods of 0, 1 and 3 months. The results are shown in tables 13 and 14 below, respectively.
Watch 13
Figure BDA0001463758400001191
TABLE 14
Figure BDA0001463758400001192
Buprenorphine acetate tetrahydrate was stable to UV and visible light for up to 3 months with only 0.1 area% purity change.
Example 9: preparation of buprenorphine free base
The method comprises the following steps: purified buprenorphine free base was prepared from approximately 100g of crude buprenorphine free base ("100 g batch") as follows. To a wet cake of buprenorphine acetate tetrahydrate (about 109g, about 182mmol, prepared from crude buprenorphine free base by the method in example 2) in a model FD100-C22 laboratory filter dryer (GL Filtration ltd., Rossington, Doncaster, UK) was charged a premixed solution of water (120mL), IPA (180mL) and aqueous ammonium hydroxide (28 wt% aqueous ammonia, 19.5g, 1.7 equivalents). The resulting slurry was stirred at 35 ℃ for 4 hours and filtered. The separated wet solid was charged with a second portion of a premixed solution of water (120mL), IPA (180mL) and aqueous ammonium hydroxide (28 wt% aqueous ammonia, 19.5g, 1.7 equiv). The resulting slurry was stirred at 35 ℃ for 4 hours and filtered. The isolated solid was cooled to a temperature of about 25 deg.C, slurried twice more in 80: 20 water: IPA (200mL), and filtered. The solid was dried in a filter drier under reduced pressure (150 torr) at 70 ℃ for 8 hours to provide buprenorphine free base as a purified white powder (78.3g, 92% yield).
Purified buprenorphine free base was prepared from approximately 65kg of crude buprenorphine free base ("65 kg batch") by scaling up method 1 above.
The purified buprenorphine free base obtained from each of the above preparations was analyzed for the wt% content of its constituents (wt% purity of the purified buprenorphine free base itself) by the HPLC procedure provided in example 7. The results are shown in Table 15.
Watch 15
Figure BDA0001463758400001201
The method 2 comprises the following steps: a model FD100-C22 laboratory filter dryer equipped with a nitrogen mass flow controller, vacuum pump, and fluid-filled heating jacket was charged with buprenorphine acetate tetrahydrate (109.82g, prepared by a method substantially equivalent to that in example 2) as a solid. The system was sealed and placed under reduced pressure of 150 torr. The nitrogen flow rate was then set to 200mL/min, the system was supplied with 65 ℃ heating fluid, and held at that temperature for 30 minutes. Next, the system was supplied with heating fluid which was gradually heated from 65 ℃ to 95 ℃ over a period of 6 h. Thereafter, the system was supplied with 95 ℃ heating fluid for 24 h. The batch temperature of the solids ranged between 67 ℃ and 70 ℃ over a 24 hour period. After cooling to 20 ℃, the resulting buprenorphine free base was expelled as a white solid (83.61g, 97% yield).
The purified buprenorphine free base obtained above was analyzed for area% content of its constituents by the HPLC procedure provided in example 7 (area% purity of the purified buprenorphine free base itself). The results are shown in Table 16.
TABLE 16
Figure BDA0001463758400001211
The method 3 comprises the following steps: a dissolution vessel containing solid buprenorphine acetate tetrahydrate (about 214mmol) was charged with IPA (5 volumes based on buprenorphine acetate tetrahydrate feed) and the blend was heated to 70 ℃ to dissolve the solids. The resulting solution was fine filtered using 0.2 μm polypropylene filter media and charged to a crystallization vessel. IPA (2 volumes) was added to rinse the dissolution vessel, the rinse solution was heated to 70 ℃, and then fine filtered. The resulting filtered rinse solution was also charged to the crystallization vessel and the vessel contents were maintained at a temperature of 60 ℃ throughout. Aqueous ammonium hydroxide (28 wt% aqueous ammonia, 19.5g, 1.5 eq) was charged to the crystallization vessel via an addition funnel. Then continuously adding anti-solvent water (5 volumes based on buprenorphine acetate tetrahydrate feed) to the crystallization vessel over a 20 minute period while maintaining a batch temperature of 60 ℃; buprenorphine free base product precipitated. The precipitate was slurried for an additional 30 minutes and the slurry was filtered at a batch temperature of 60 ℃ to provide buprenorphine free base as a solid. The solid was reslurried twice in 80: 20 water: IPA (2 volumes) to remove ammonium acetate and filtered to provide buprenorphine free base as a white solid. The solid was dried in a vacuum drying oven at sub-atmospheric pressure (150 torr) at 70 ℃ for 8h to provide purified buprenorphine free base as a white powder. Almost the same experiment had 93% yield.
The method 4 comprises the following steps: buprenorphine acetate tetrahydrate (1.00g) was heated in water (10mL) in a capped vial at 80 ℃ for 3 hours. The slurry was filtered while hot and washed twice with 2mL warm water (50 ℃). The product buprenorphine free base was air dried (0.61g, 78% yield).1H NMR(CD3OD) confirmed the product as free base with traces of acetic acid.
The method 5 comprises the following steps: buprenorphine acetate tetrahydrate (10.53g) was charged to a flask containing heptane (60mL), where the flask was equipped with a Dean-Stark trap. The solution was refluxed for 3.5 h; the reflux temperature is in the range of 86 ℃ to 99 ℃. The trap collected 1.85mL of liquid (2.2 mL for theoretical amount of acetic acid and water). The mixture was cooled, filtered, washed with heptane and air dried to provide the free base form (8.00g, 98% yield).1H NMR(CD3OD) confirmed the product as free base with traces of acetic acid.
The invention is not intended to be limited in scope by the particular embodiments disclosed in the examples which are intended as illustrations of various aspects of the invention, and any embodiments which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to be within the scope of the appended claims.
All publications, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent application, or other document were individually indicated to be incorporated by reference for all purposes.

Claims (56)

1. An acetate salt of buprenorphine, comprising a hydrate, wherein the hydrate is a tetrahydrate.
2. A crystalline form of the acetate salt of buprenorphine of claim 1, characterized by an X-ray powder diffraction pattern obtained by exposure to cuka radiation comprising peaks at 2 Θ angles substantially equal to at least the peaks at 8.77, 10.31, 16.21, 18.47, and 18.70, and having at least one additional peak at 2 Θ angles substantially equal to 6.38, 11.93, or 19.40.
3. The crystalline form of claim 2, characterized by an X-ray powder diffraction pattern obtained by exposure to CuK α radiation comprising peaks at diffraction angles substantially equal to the peaks at least at those positions in the following table:
position 2 theta] 6.38 8.77 10.31 11.93 16.21 18.47 18.70 19.40
。
4. The crystalline form of claim 2, having an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in figure 4 when measured using CuK α radiation.
5. The crystalline form of any one of claims 2 to 4, wherein the crystalline form exhibits a first transition region having at least one peak position at 50 ℃ to 140 ℃ as measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute.
6. The crystalline form of any one of claims 2 to 4, wherein the crystalline form exhibits a second transition region having a peak position at 217 ℃ to 225 ℃ as measured by a heat flow differential scanning calorimeter at a heating rate of about 10 ℃/minute.
7. The crystalline form of claim 6, which exhibits an integral ratio of the first transition region at 50 ℃ to 140 ℃ relative to the second transition region at 217 ℃ to 225 ℃ of 7 to 8, wherein the integral is determined over a temperature range of 35 ℃ to 180 ℃ and 203 ℃ to 233 ℃, respectively.
8. The crystalline form of claim 7, wherein the crystalline form exhibits an integral ratio of from 7.1 to 7.8.
9. The crystalline form as claimed in any one of claims 2 to 4, characterized in that it is a monoclinic crystal.
10. The crystalline form of claim 9, wherein the unit cell parameter is
Figure FDA0002498274790000026
Figure FDA0002498274790000021
And is
Figure FDA0002498274790000022
11. The crystalline form of claim 9, wherein the unit cell parameter is
Figure FDA0002498274790000025
Figure FDA0002498274790000024
And is
Figure FDA0002498274790000023
12. The crystalline form of claim 9, wherein the space group is P21。
13. A pharmaceutical composition comprising the acetate salt of buprenorphine of any one of claims 1 to 12, and a pharmaceutically acceptable carrier.
14. A process for the preparation of an acetate salt of buprenorphine as defined in any of claims 1 to 12, the process comprising the steps of:
(a) contacting buprenorphine free base with a solution comprising acetic acid in a dissolution vessel to form a blend, wherein the blend is at a temperature of 40 ℃ to 80 ℃;
(b) optionally filtering the blend of step (a);
(c) adding a reagent to the blend produced in step (a) or (b) to precipitate the acetate salt of buprenorphine; and
(d) isolating the acetate salt of buprenorphine precipitated in step (c).
15. The method of claim 14, wherein in step (a) the buprenorphine free base is contacted with from 2 mass equivalents to 6 mass equivalents of the solution comprising acetic acid relative to the starting mass of the free base.
16. The method of claim 14, wherein the buprenorphine free base is contacted with from 3 mass equivalents to 5 mass equivalents of the solution comprising acetic acid relative to the starting mass of the free base.
17. The method of any one of claims 14 to 16, wherein the solution comprising acetic acid is an aqueous solution.
18. The method of claim 17, wherein the aqueous solution has 40 to 70 wt% acetic acid relative to the weight of the aqueous solution.
19. The method of claim 17, wherein the aqueous solution has 45 to 60 wt% acetic acid relative to the weight of the aqueous solution.
20. The method of any of claims 14 to 16, wherein in step (a) the admixture is at a temperature of from 40 ℃ to 80 ℃ for a period of time such that a substantial portion of the buprenorphine free base has dissolved.
21. The method of claim 20, wherein in step (a) the admixture is at a temperature of 45 ℃ to 75 ℃ for a period of time such that a substantial portion of the buprenorphine free base has dissolved.
22. The method of claim 20, wherein in step (a) the admixture is at a temperature of 50 ℃ to 70 ℃ for a period of time such that a substantial portion of the buprenorphine free base has dissolved.
23. The method of any of claims 14 to 16, wherein in step (a) the admixture is agitated to accelerate dissolution of the buprenorphine free base.
24. The method of claim 14, wherein the blend of step (a) is filtered in step (b) in a filtration device.
25. The method of claim 24, wherein in step (b), the blend of step (a) added to the filtration device is at a temperature of 40 ℃ to 80 ℃.
26. The method of claim 24, wherein in step (b), the blend of step (a) added to the filtration device is at a temperature of 45 ℃ to 75 ℃.
27. The method of any one of claims 24 to 26, wherein an additional volume of solution comprising acetic acid is used to flush the dissolution vessel, the filtration device, or the dissolution vessel and the filtration device.
28. The method of claim 27, wherein the additional volume of the solution comprising acetic acid is 0.1 mass equivalents to 2.0 mass equivalents relative to the starting mass of the buprenorphine free base in step (a).
29. The method of claim 27, wherein the additional volume of the solution comprising acetic acid is 0.3 mass equivalents to 0.5 mass equivalents relative to the starting mass of the buprenorphine free base in step (a).
30. The method of claim 27, wherein the additional volume of the solution is an aqueous acetic acid solution.
31. The method of claim 30, wherein the additional volume of the solution comprising acetic acid is an aqueous solution comprising acetic acid present at 40 wt% to 70 wt% relative to the weight of the solution.
32. The method of any one of claims 14 to 16, wherein in step (c), the reagent is selected from the group consisting of an anti-solvent, seed crystals, and combinations thereof.
33. The method of claim 32, wherein the reagent comprises an anti-solvent.
34. The method of claim 33, wherein the anti-solvent comprises water.
35. The process of claim 33 or 34, wherein 0.2 to 8.0 mass equivalents of anti-solvent relative to the starting mass of free base in step (a) is added to the blend of step (a) or (b).
36. The method of claim 33 or 34, wherein the anti-solvent is added within 10 ℃ of the temperature of the blend of step (a) or step (b).
37. The method of claim 36, wherein the anti-solvent is added at a temperature within 5 ℃ of the temperature of the blend of step (a) or step (b).
38. The method of claim 32, wherein the reagent comprises seed crystals.
39. The method of claim 38, wherein the seed crystals comprise an acetate salt of buprenorphine.
40. The method of claim 39, wherein 0.1 to 5.0 wt% seed crystal relative to the starting mass of the buprenorphine free base in step (a) is added to the blend of step (a) or (b).
41. The method of any one of claims 38-40, wherein the blend of step (a) or (b) is at a temperature of 40 ℃ to 80 ℃ when the seed crystals are added.
42. The method of claim 41, wherein the blend of step (a) or (b) is at a temperature of 55 ℃ to 65 ℃ when the seed crystals are added.
43. The method of claim 32, wherein a first amount of the anti-solvent is added followed by the addition of the seed crystals.
44. The method of claim 43, wherein the adding the seed crystals is followed by adding a second amount of the anti-solvent.
45. The method of claim 43 or 44, wherein the first amount of the antisolvent is 0.2 mass equivalents to 2.0 mass equivalents relative to the starting mass of the buprenorphine free base in step (a).
46. The method of claim 43 or 44, wherein 0.1 to 5.0% by weight of the seed crystal is added relative to the starting mass of the buprenorphine free base in step (a).
47. The method of claim 44, wherein the second amount of anti-solvent is 1.0 mass equivalents to 6.5 mass equivalents relative to the starting mass of the buprenorphine free base in step (a).
48. The method of any of claims 14-16, further comprising cooling the admixture to a temperature of 30 ℃ or less after adding the reagent and prior to isolating the acetate salt of buprenorphine in step (d).
49. The method of any of claims 14-16, further comprising adding a co-solvent to the admixture after the precipitating of step (c) and prior to isolating the acetate salt of buprenorphine in step (d).
50. The method of claim 49, wherein the co-solvent is selected from the group consisting of methanol, ethanol, isopropanol, and combinations thereof.
51. The method of claim 49, wherein the co-solvent is isopropanol.
52. The method of any of claims 49-51, further comprising cooling the admixture to a temperature of 30 ℃ or less after adding the co-solvent and prior to isolating the acetate salt of buprenorphine in step (d).
53. The method of any one of claims 14 to 16, wherein the separation in step (d) is achieved by filtration.
54. The method of any of claims 14-16, further comprising slurrying the isolated acetate salt of the buprenorphine obtained from step (d) with a slurrying solution comprising water and an alcohol, and filtering the acetate salt therefrom.
55. Use of an acetate salt of buprenorphine as claimed in any of claims 1 to 12 in the manufacture of a medicament for the treatment of pain.
56. An acetate salt of buprenorphine as claimed in any of claims 1 to 12 for use in the treatment of pain.
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